Fat-Soluble Antioxidant Dynamics: The Beta Carotene Enigma Explained

Tagged:  

Is beta carotene safe?

Are fat blockers and artificial fats safe?

Should cholesterol be raised or lowered?

What is the overlooked family of carotenoids?

Why is there an epidemic rise in macular degeneration?

Can smokers avoid lung cancer with nutritional supplements?

How do cholesterol-lowering drugs increase the risk of cancer?

How do viruses, intestinal bacteria and estrogen control the delivery of fat-soluble antioxidants to tissues?

Should nutritional supplements contain a full array of carotenoids and tocopherols (vitamin E)?

All these questions can be answered by understanding fat-soluble antioxidant dynamics.

Introduction

While beta carotene-rich foods have been shown to reduce the risk of many forms of cancer, recent studies have caused researchers to question the cancer-fighting properties of synthetic beta carotene or high-dose beta carotene in nutritional supplements, particularly among at-risk individuals such as smokers. A similar situation may exist with vitamin E where dietary sources, but not supplements, have been found to reduce the risk of breast cancer.( 1)

A review of over 200 published research studies shows a relationship between fruit and vegetable consumption and protection against most types of cancer. Increased consumption of these fresh foods is strongly advised.( 2) The fact that three recently published studies now show that beta carotene supplements did not reduce the risk of cancer and may have slightly increased the risk of lung cancer among smokers,( 3) has prompted nutritional supplement manufacturers to respond. They suggest the clinical trials may have been poorly designed (they were); that the dosage of beta carotene may have been insufficient (it was the right dose but the wrong carotenoid); and that beta carotene may prevent the onset of lung cancer but may not be effective in reversing long-standing malignancies.( 4) One nutrition industry association executive is quoted as saying the supposition that beta carotene can reverse the ravages of cigarette smoking is ridiculous -- "No one has ever suggested that beta c arotene cures lung cancer."( 5) Yet it is the purported cancer-fighting properties of beta carotene that spurred nutritional supplement manufacturers to include it in their formulas. (Note: researchers measure their results in relative numbers, not hard numbers. Thus the 18% relative increase in lung cancer deaths reported among male Finnish smokers who took beta carotene supplements requires interpretation. Actually 4.144% of beta carotene users and 3.596% of placebo users died of lung cancer, less than one-half of 1% difference. The public should not be so quick to be scared away from beta carotene.)

Because of its vitamin A activity beta carotene was assumed to be the primary cancer fighter, particularly because there is six times as much beta carotene as alpha carotene found in the body.( 6) And the role of beta carotene in preventing the oxidation (hardening) of LDL "bad" cholesterol within blood vessel walls has been demonstrated in the prevention of coronary artery disease,( 7) further substantiating beta carotene as a disease fighter.

When prestigious medical journals like the New England Journal of Medicine published reports in the mid-1980's that beta carotene has anticancer properties, the National Cancer Institute thought enough of beta carotene to launch clinical studies of its effectiveness. Nutritional product manufacturers were quick to add beta carotene to most daily vitamin formulas. Low intake of fruits and vegetables which contain beta carotene is consistently associated with an increased risk of lung cancer in both prospective and retrospective studies,( 8) so the attention given to beta carotene as a protective agent for smokers was based on an assumption that beta carotene is the primary protective antioxidant.

The importance of another class of carotenoids as disease fighters, specifically the xanthophylls, may have been overlooked. As early as 1985 it was known that non-vitamin A carotenoids from foods (tomatoes, strawberries) were responsible for a reduction in cancer deaths and that no association between beta-carotene-rich foods (squash, carrots) and reduced cancer risk was found. The researchers in this 1985 study said: "Some factor, present in green and yellow vegetables, other than carotene, may be providing the protective effect which we and others have observed."( 9)

When rodents are administered a toxic agent, 93% develop mammary tumors, but when they are pretreated with low doses of a non-vitamin A carotenoid (canthaxanthin, an approved food coloring agent derived from crustaceans), a 65% reduction in tumor formation was reported.( 10) In another animal study, vitamins C and E reduced tumor counts in animals exposed to a carcinogenic chemical but beta carotene had no effect. Beta carotene along with two other non-vitamin A carotenoids (phytoene and canthaxanthin) are able to delay or decrease the number of skin tumors induced by ultraviolet radiation.( 12) There is additional evidence that non-vitamin A carotenoids are protective against other diseases. For example, the first detectable sign of glaucoma is the extinction of xanthophylls from the peri-macular area of the retina.( 13) Xanthophylls comprise the primary antioxidant pigment found at the center of the retina and removal of xanthophylls from the diet accelerates the onset of macular degeneration, a now common sight-threatening disease.( 14)

Xanthophylls are yellow pigments that predominate over beta carotene in certain foods like kale, spinach and amaranth. Only recently have laboratory methods been devised to delineate the various carotenoids. Kohlmeier and Hastings suggest beta carotene may only be a marker of consumption of other carotenoids (such as lycopene from tomatoes and lutein from spinach) or phenolic compounds (such as quercetin from onions).( 15)

More sophisticated spectrophotometric laboratory methods have identified lutein in the xanthophyll family as the other major dietary carotenoid which is more abundant in many foods than beta carotene. Lutein has only 5% of the vitamin A activity as beta carotene,( 16) but apparently is a target antioxidant, accumulating or having protective properties in certain tissues throughout the body, such as the lung and retina. Lutein is a potent counter agent against lipid peroxidation,( 17) the most hazardous form of oxidation that attacks fatty membranes throughout the body.

There are two branches of the carotenoid family, the carotenes and the xanthophylls. Beta carotene is the predominant carotenoid in tuberous yellow-orange vegetables, such as carrots, squash, yams and sweet potatoes, and promotes vitamin A synthesis in the liver. Lutein and zeaxanthin are the predominant xanthophylls provided by green leafy vegetables like spinach and kale. Together lutein and beta carotene comprise over 80% of all carotenoids, whereas alpha carotene, cryptoxanthin and lycopene are infrequently encountered or occur in small concentrations.( 18)

There are dynamic factors at work within the body which influence the ability to absorb, metabolize, transport and store fat-soluble antioxidants. Carotenoids are fat-soluble nutrients. A little fat in the diet is required for the absorption of beta carotene.( 19) A little bit of olive oil can improve absorption of carotenoids by fivefold (from 5% to 25%).( 20) Dietary fiber, and cholesterol-lowering drugs may significantly inhibit carotenoid utilization. These dynamic factors have apparently gone unrecognized by those who design clinical studies, though they are well-documented in the medical literature. The failure to recognize these dynamic factors may be responsible for recent clinical trials which have reported that supplemental beta carotene is of no value, and may in fact slightly increase the risk of lung cancer among smokers.

The toxicity of beta carotene is low.( 21) Smoking and excessive alcohol consumption are hazardous, not beta carotene consumption per se. Vitamins A, D, E and K join carotenoids in the family of fat-soluble nutrients. The recognized competition for absorption among fat-soluble antioxidants, documented below, now makes it imperative that nutritional supplements provide an array of fat-soluble antioxidants. Or the staggered ingestion of carotenoids and other fat-soluble nutrients may be recommended at different times of the day to enhance absorption and tissue availability. Based upon the data provided in this article, manufacturers of daily multivitamins need to take corrective action. In some cases where nutrient absorption is impaired (gastrointestinal disease, liver disease, low circulating cholesterol), the administration of water-soluble forms of vitamins A and E may be helpful in nutrient replenishment.

Dietary and non-dietary factors affecting the absorption and utilization of carotenoids

Dietary factors

Digestibility of food matrix

Particle size of food

Fat level -- bile acid secretion

Antioxidant level, especially vitamin E

Dietary fiber level and type

Level of carotene in meal

Interactions with other carotenoids

Protein level and status

Iron, zinc status

Vitamin A level and status

Others?

Non-dietary factors

Intestinal malabsorption (lipase, gastric resection)

Intestinal bacterium: heliobacter pylori

Hormone status (thyroid, estrogen)

Tobacco

Sunlight exposure

Age

Drug interactions

Alcohol

Cholesterol-lowering

Fat blockers

Artificial fats

Liver or kidney disease

Adapted from Erdman JW, Bierer TL, Gugger ET, Absorption and transport of carotenoids, in Carotenoids and Human Health, NY Academy Sciences 1993; 691: 76-85.

Foods or Supplements: What Are We to Think of Beta Carotene?

The news reports emanating from the National Cancer Institute which advised the public to acquire beta carotene from fresh foods and avoid nutritional supplements makes as much sense as warning the public away from eating a carrot every day.

But what are we to think of beta carotene? Does this negative information derail the antioxidant revolution and the growing movement towards taking nutritional supplements? Given that cancer is prevalent in populations over age 70, and human populations which consume beta carotene-rich foods appear to acquire some protection against malignancies, the National Cancer Institute continues to suggest that beta carotene be acquired from a diet of fruits and vegetables rather than supplements. Yet a recent study shows that no more than 12% of US adults consume the recommended portions of fresh fruits and vegetables on a daily basis.( 22)

There is a strong argument for supplementation buoyed by the fact that older adults may eat less volume of food, and frequently do not absorb nutrients as they did when they were younger.( 23) Sub-clinical nutrient deficiencies are frequently found among older adults, who aside from smokers are most prone to develop cancer. A recent study of nursing home patients reveals four of their five most disliked foods were spinach, brussels sprouts, rice and cooked cabbage,( 24) the very foods the National Cancer Institute recommends!

Virtually every major daily multivitamin contains beta carotene. Should synthetic beta carotene be removed from these formulas, to be replaced with a natural carotenoid complex, or will reducing the dosage resolve the problem? What does one make of carrots, which contain about 10,000 units of vitamin A activity? How could a carrot be healthy but a synthetic version of beta carotene be of little or no benefit? Recent data concerning supplemental beta carotene does not hinder the "antioxidant revolution," it just gives more insight into its workings.

What About Vitamin A?

Why don't nutritional supplement manufacturers provide vitamin A rather than its precursor, beta carotene, in daily vitamins? For some time it has been known that high-dose vitamin A may act as a teratogen, that is it increases malformation among fetuses. Aware of this potential problem, in 1987 the Council for Responsible Nutrition advised supplement manufacturers to limit the dosage of vitamin A to 10,000 units per day and many manufacturers switched to beta carotene.( 25) Recently it was confirmed that 10,000 units of preformed vitamin A a day taken by fertile women more than doubles the risk (to one in 60) of having a baby with birth defects.( 26)

There is considerable interest in vitamin A as an anticancer weapon. On November 29, 1995 the Wall Street Journal reported that Roche Holdings Ltd. received FDA approval for Vesanoid, a chemical derivative of vitamin A which "has the unique ability to turn cancerous cells into normal ones." Vesanoid has won FDA approval in the treatment of a rare form of leukemia called acute promyelocytic leukemia. Vesanoid is said to improve the five-year survival rate from this form of leukemia from 25% with chemotherapy alone to 75% with chemotherapy and the vitamin A drug.( 27) This report goes on to say that Roche, also a primary manufacturer of beta carotene, is studying other retinoids for anticancer properties, in particular Accutane which is a prescription remedy for acne. Will these vitamin A drugs result in the same problems posed by high-dose synthetic beta carotene?

The public is frequently warned of vitamin A overdosage. Just one case of vitamin A toxicity receives attention in medical journals,( 28) though between 1976 and 1987 only an average of 10 cases/year of toxic overdose of vitamin A have been reported.( 29) The pharmaceutical companies are poised to offer their derivations of vitamin A as anticancer weapons. These drugs are not without side effects. Accutane can produce the same signs as hypervitaminosis A. Among patients taking Accutane for acne, 3 of 50 patients reported abnormal night vision (a sign that lutein in the retina is in short supply).( 30)

Blood vs. Tissue Levels of Vitamin A

Given that many epidemiological studies are based upon a single sample of blood taken on a given day, one has to question some of the conclusions drawn from these studies, whether positive or negative. Among well-nourished populations, even when taking up to 25,000 IU of preformed vitamin A (more than five times normal daily dietary intake), no increase in blood levels was observed, and among women with low plasma levels who took 10,000 IU of vitamin A, they showed only a 9% increase in blood levels.( 31)

Blood tests may not reveal the density of fat-soluble antioxidants in tissues. Plasma concentrations of nutrients reflect short-term intake while cellular concentrations provide a better picture of long-term tissue supply. Furthermore, upon supplementation the concentration of various carotenoids may increase in one group of cells or tissues which may not represent their concentration in another groups of cells or tissues. In a group of male physicians, beta carotene comprised 30.5% of total carotenoids in blood plasma, lutein 24.9%, lycopene 22.0% and cryptoxanthin 15.8% and alpha-carotene 6.2%. However, in red blood cells lutein comprised 60% of total carotenoids. Despite supplementation with beta carotene, lutein remained the predominant carotenoid in red cells (43.3%) over beta carotene (30.2%) concentration.( 32) The concentration of carotenoids is highest in the corpus luteum (about 60 micrograms/gram) and adrenal glands(20 micrograms/gram). While the total body pool of c arotenoids is 100-150 milligrams in a well nourished person, only 1% reside in the circulating blood serum.( 33) Serum levels of lutein have been measured to vary by a factor of 19 (2.0-38.2 micrograms/deciliter).( 34) The blood stream may carry very little lutein, but lutein is slowly deposited in tissues like the retina and adrenal glands where its concentration is relatively high. Regarding vitamin E, M.K. Horwitt also notes that only 1% of this nutrient is found in the circulation.( 85) So there are limitations on the use of blood tests to determine deficiencies.

Fat-soluble nutrient imbalance or deficiencies do not readily become apparent. The fat-soluble antioxidants are apparently so essential for life that the body stores them so they are not in short supply at any given time. After 68 days of a very-low carotenoid diet, measurable though reduced concentrations of all carotenoids remain in plasma.( 35) With the complete absence of dietary sources of vitamin A, plasma levels of vitamin A will not drop for 22-220 days because of liver stores.

Using blood samples, only a frank deficiency of fat-soluble antioxidants can be detected. In other words, the oil reservoir may be low but the gauge doesn't register this fact until it's totally dry. A clinician looking at a normal blood level of vitamin A or E can be easily fooled. It's like saying the oil gauge on an airplane reads normal but there may be a longstanding low oil level. The oil problem can't be detected till the plane completely loses oil pressure, but the moving parts haven't been adequately lubricated for a long time and friction has caused damage.

Liver reserves of vitamin A are the best indicator of vitamin A status, not blood plasma levels.( 36) Vitamin A absorption varies from 7 to 67%. In 1970 researchers assayed the livers of deceased individuals to determine their actual vitamin A content. "Acceptable" levels of vitamin A ranged from 100-300 micrograms/gram of wet tissue. Livers obtained from diseased subjects contained less vitamin A than those of accident victims.( 37)

Because foodstuffs contain variable amounts of nutrients, because demands for these nutrients vary widely between individuals, and because deficiencies of fat-soluble antioxidants are difficult to identify and may be long-standing before detection, supplementation by the population at large is a justifiable approach to health maintenance.

The Advantages of a Diet with Varied Consumption of Carotenoids vs. Consistent Provision of Supplemental High-Dose Beta Carotene

The daily diet only provides as little as 3 milligrams of vitamin E, less than the RDA of 12-15 milligrams and less than the 100-800 units of vitamin E now recommended for at-risk individuals to reduce their risk of heart attack.( 38) As noted below, the daily intake of beta carotene can be as low as 587 micrograms, not even one full milligram. The RDA for vitamin A is 5000 units. Intake of xanthophylls is less than beta carotene. So the idea of supplementation to fortify the daily diet seems reasonable.

The advantage of obtaining nutrients from foods is that the normal rotation of foods provides irregular intake of fat-solubles without constant domination by one particular nutrient. Individuals with a varied diet consume widely differing daily amounts of carotenoids and vitamin E and their blood plasma levels of these nutrients vary accordingly. For example, daily plasma beta carotene levels can vary by a factor of 11 ( 12-131ug/dL), alpha tocopherol (vitamin E) by a factor of nearly three (526-1471ug/dL). Consumption of beta carotene varies by a factor of 16 (587-9893ug/day) and vitamin E by a factor of nine ( 3-29mg/day).( 39)

Fat-soluble vitamins (vitamins A, D, E, K) and the carotenoids (carotenes from tuberous vegetables such as alpha, beta and gamma carotene, and xanthophylls (such as lutein/zeaxanthin, astaxanthin, canthaxanthin, etc.), and lycopene from tomatoes, all compete for absorption in the gastric tract and are stored in or pass through the liver where they are transported to tissues within cholesterol molecules.( 40) By varying the daily diet, the absorption of these fat-soluble nutrients is enhanced. Thus, eating a couple of carrots would supply an ample dosage of vitamin A from beta carotene, but would impair the absorption and availability of lutein. However, when eating corn, spinach or kale the next day, unopposed by competing beta carotene-rich foods, the absorption of xanthophylls is enhanced.

Healthy nonsmoking premenopausal women with mid-range cholesterol levels who ate 5-6 servings of fruits and vegetables daily increased their serum levels of provitamin A carotenoids by 90146% and serum lutein and lycopene by 31-58%. Their diets provided 3 mg./day of lutein/zeaxanthin, 12 mg./day lycopene; 2 mg./day alpha carotene, 0.5 mg./day cryptoxanthin and 6 mg./day beta carotene. There was a great variance among the participants in this study, with 29% classified as low responders, i.e. had significantly smaller increases in serum carotenoid levels. The greatest difference between high responders and low responders was for beta carotene (66% difference) while the difference for lutein was moderate (35%).( 41) The reasons for this variability in absorption of carotenoids may have considerable impact on individual vulnerability to disease.

Daily supplementation of a single purified carotenoid, such as high-dose beta carotene, may erase lutein from the picture. Purified canthaxanthin nearly obliterates liver levels of lycopene, the red pigment derived from tomatoes.( 42) A woman who ate few beta carotene-rich foods but who consumed 2 liters of tomato juice for several years developed yellow skin and liver discoloration caused by lycopene (the predominant carotenoid pigment in tomatoes). In rodent studies large amounts of lycopene can inhibit the conversion of carotene to vitamin A, probably by competitive inhibition.( 43) When healthy adults were given a carotenoid mix containing 8.5 mg. of beta carotene, 3.5 mg. of alpha carotene and 0.5 mg. of lycopene per day, alpha and beta carotene blood levels increased but lycopene did not.( 44) Micozzi and colleagues report that individuals who took purified beta carotene in 12 or 30 mg. capsules experienced a significant drop in plasma lutein, a finding attributed to impaired intestinal absorption.( 45)

In another study, large-dose beta carotene did not reduce the amount of vitamin E or coenzyme Q10 in circulating LDL molecules, but synthetic beta carotene reduced the concentration of lycopene in LDL by 25% whereas natural beta carotene reduced lycopene by only 12% (not statistically significant).( 46)

Contrary to the widespread assumption, dark green leafy vegetables do not significantly improve vitamin A status.( 47) Because many foods which contain beta carotene also contain significant amounts of lutein (spinach, Swiss chard, kale, red peppers), some researchers now believe lutein is the primary carotenoid responsible for the cancer risk reduction observed among study groups who eat plentiful amounts of fresh fruits and vegetables.( 48)

It would be instructive to find populations where the consumption of lutein is high and analyze the rates of lung cancer among smokers. Such a population exists in the Fiji Islands where 80% of Fijian men smoke and the daily consumption of lutein from dark green leafy vegetables is unusually high. The lung cancer rate on Fiji is one fourth or less than other South Pacific Island countries. Whereas the daily consumption of lutein from dark green leafy vegetables ranges from 3,508-8,664 micrograms in Hawaiians, Tahitians and Cook Islanders, in Fiji average lutein consumption ranges from 23,647 to 25,672 micrograms in Fijian women and men respectively ( 3-6times more lutein than other South Pacific Islanders). The ratio of lutein to beta carotene is also revealing. Fijians consume one-third to two-thirds more lutein than beta carotene in their daily diet. The consumption of beta-carotene-rich yellow-orange vegetables showed a slight but statistically insignificant increase in lung cancer rates among Fijian smokers. In contrast to beta carotene, lutein dramatically decreases the risk of lung cancer among Fijian smokers when calculated as an independent variable apart from daily cigarette usage, etc. In all 8 previous case-control studies and 1 of 2 past cohort studies a protective effect against lung cancer was noted for dark green leafy vegetables.( 49) This data is consistent with the findings of the beta carotene supplementation study among heavy smokers in Finland which reported a slight statistical increase in lung cancer rates.

That lutein is a target antioxidant for the lungs is apparent by the fact that cancer rates for other sites, liver, cervical and ovarian, are similar to rates of other Polynesians.

Smoking, Vitamin E and Carotenoids

Smoking throws a whole new set of dynamics into the antioxidant soup bowl. Ross and colleagues studied Scottish male smokers who were not receiving nutritional supplements or medication.( 50) These smokers consumed an average of 19 cigarettes per day and 11.3 alcoholic beverages per week compared to a control group who did not smoke and consumed an average of 6.4 alcoholic beverages weekly.

Blood plasma antioxidant levels of smokers and nonsmokers who did not consume nutritional supplements

Smokers Nonsmokers

P=

Vitamin C uM

* 25.6
* 37.6
* 0.003

Alpha

carotene ug/ml

* 0.042
* 0.061
* 0.0006

Beta

carotene ug/ml

* 0.26
* 0.32
* 0.026

Lutein/

zeaxanthin ug/ml

* 0.24
* 0.29
* 0.052

B-Cryptoxanthin

ug/ml

* 0.042
* 0.063
* 0.041

In the above study the levels of vitamin A, E and lycopene were not significantly different between smokers and nonsmokers. Smoking only slightly reduced circulating lutein levels. The researchers in this report suggest that smokers increase their intake of carotenoids "only within the nutritional range, since high doses of B-carotene (20 mg/day for 5-8 years) have been associated with increased incidence of lung cancer in long-term smokers." One of the fallacies of this advice is the false belief that blood levels of carotenoids always reflect tissue levels. They do not, as evidenced in the retina and elsewhere. Another, as previously stated, is the false belief that beta carotene is the sole anticancer agent.

In other studies cigarette smoking and alcohol intake have been shown to have little impact on blood levels of vitamin E, but reduce circulating beta carotene.( 51-52) Smokers have low levels of carotenoids in their blood even after adjusting for differences in dietary intake.( 53) This is consistent with the study of Finnish males which showed that beta carotene was ineffective in reducing the risk of lung cancer but vitamin E was effective at reducing the risk of prostate cancer.

When freshly obtained blood plasma is exposed to cigarette smoke, fat-soluble antioxidants disappear in this order: lycopene > alpha-tocopherol > trans-B-carotene > lutein + zeaxanthin/cryptoxanthin > gamma tocopherol.

Smokers exhibit about half of the density of yellow macular pigment (lutein and zeaxanthin) at the back of their eyes compared to nonsmokers.( 55) Smokers develop macular disease about 7 years sooner than non-smokers.( 56)

Brown is the first to report that smoking cessation brought about an unexpected increase in gamma-tocopherol (variety of vitamin E). Non-statistical rises in vitamin C, alpha and beta carotene plasma levels were also noted upon smoking cessation. Brown notes that vitamin E supplementation may reduce levels of gamma-tocopherol, as supplements often only contain alpha-tocopherol rather than mixed tocopherols. While gamma-tocopherol is the predominant form of vitamin E in Western diets it has about one-tenth to one-fifth the biological activity of alpha-tocopherol. Smokers may benefit from mixed tocopherols rather than alpha-tocopherol alone.( 57) Among healthy adults who were given 1200 IU of alpha-tocopherol, within 8 weeks their gamma-tocopherol plasma levels decreased by 30-50% from initial values.( 58) In clinical studies with smokers the provision of supplemental alpha-tocopherol alone is in question. Just because gamma-tocopherol disappears more quickly from the circulation than does alpha tocopherol doesn't mean gamma-tocopherol doesn't make a significant contribution to total vitamin E activity. Bieri and Evarts indicate gamma-tocopherol contributes about 20% of the vitamin E activity from the diet. Compared to plasma levels, gamma-tocopherol is in four times greater concentration in the lung, six times greater in the heart and nearly ten times greater in adipose tissue.( 59) In red blood cells, alpha-tocopherol and gamma-tocopherol can inhibit the destruction of red cells caused by hydrogen peroxide, though gamma tocopherol does this to a lesser extent.( 60) Supplementation of alpha-tocopherol reduces gamma-tocopherol levels.( 61) In one study of nonsmokers, when 1200 IU of alpha-tocopherol was given for 8 weeks, plasma gamma-tocopherol was typically reduced by 30-50%.( 62)

It has long been questioned why certain populations of smokers, like the Japanese, do not have the same high lung cancer rates as other populations.( 63) While other factors such as fatty acid consumption from fish are likely to be involved as well, it appears the provision of xanthophylls along with carotenes in the diet is of importance. Readers can quickly see how tobacco companies could misuse this information to claim that dietary deficiencies and not their cigarettes are responsible for the lung cancer epidemic. Tobacco growers could say: "It was your diet and not our cigarettes that caused lung cancer." To guard against this occurrence, this reporter suggests use of the proper logic. Tobacco is a known cause of lung cancer (carcinogen). Carotenoids are negatively associated with cancer and when in short supply an increase in cancer rates may be observed among smokers.

Despite the current confusion by supplement manufacturers, the provision of antioxidant supplements to delay or prevent disease should not be ridiculed. It is the cancer researchers themselves who have proposed the use of supplements in clinical studies, the long-term results of which are now becoming known. As early as 1980 review articles pointing out the interaction between beta carotene and vitamin E were available to researchers. The simultaneous presence of beta carotene and high-dose vitamin E can suppress the conversion to retinol (form of vitamin A).( 64)

Despite the encouraging data presented in this report which shows that populations of smokers in Japan and the Fiji Islands do not have high lung cancer rates due to nutritional factors, this journalist believes emphasis should be placed on smoking cessation and limitation of alcohol consumption rather than the failure of nutritional supplements to subdue long-standing disease processes like lung cancer.

High-Dose Beta Carotene and Retinal Disease

If high-dose beta carotene impairs lutein availability, and lutein is an essential retinal pigment for the maintenance of the visual system, is there any evidence that subjects who take high-dose beta carotene experience visual problems?

The administration of 45 mg. of daily beta carotene for 18 days by a 60-year old male resulted in blurred vision, advancement of presbyopia (the need for reading glasses), and occasional double vision (a sign of vitamin A toxicity). This individual had a history of poor night vision.( 65) Long-term administration of high-dose carotenoids for skin diseases has also been reported to result in prolonged dark adaptation.( 66) It is apparent that high-dose beta carotene impairs the availability of protective yellow retinal pigment in some individuals, most likely blue-eyed female smokers who are already known to have half as much of this protective retinal pigment.( 67) The consumption of high-dose beta carotene without accompanying lutein among, individuals with any retinal disease should be called into question. Lutein should exceed beta carotene, as it does in spinach, kale and other vegetables where high consumption has been found to reduce the risk of macular disease( 68) and catara cts.( 69) Even then, to ensure absorption and availability, consumption of supplemental lutein may have to be confined to a separate meal time unopposed by beta carotene or other fat-soluble vitamins among macular disease subjects.

Relationship Between Beta Carotene and Vitamin E

The competition between fat-soluble antioxidants is exhibited in a clinical study of retinitis pigmentosa (RP) patients who took 15,000 units of vitamin A, or 15,000 units of vitamin A accompanied by 400 units of vitamin E. RP is a disease characterized by onset of night blindness believed to be induced by abnormal vitamin A metabolism. RP patients who took vitamin A alone experienced a significant decrease in the progression of visual loss as measured by an electroretinogram. When vitamin A and E were administered together, the observed benefit diminished.( 70) The advice given to RP patients by the RP Foundation suggests 15,000 daily units of vitamin A palmitate (J.R. Carlson Laboratories, Arlington Heights, Ill.) and the avoidance of large-dose vitamin E supplements.( 71)(*)

Joe and Teresa Graedon, in their book The People's Guide To Deadly Drug Interactions (St. Martin's Press, New York 1995), indicate long-term supplementation of beta carotene, in doses ranging from 1560 mg. lowers blood levels of vitamin E significantly. In a contrary study, a 30 mg. supplement of beta-carotene did not affect blood plasma levels of alpha-tocopherol,( 72) so other previously listed factors may be involved. Plasma levels of vitamin E are lower when animals are fed beta carotene with 16% corn oil than animals fed beta carotene and 5% corn oil. The most dramatic drop in vitamin E is observed when high corn oil, beta carotene and vitamin A are administered together.( 73) Excessive vitamin E intake seems to impair carotenoid absorption while vitamin E deficiency decreases vitamin A formation, perhaps because adequate vitamin E is required to protect carotenoids and vitamin A from oxidation.( 74) This data again serves to underscore the importance of providing tocopherols (vitamin E) with mixed carotenoids.

So how much vitamin E should be consumed daily? Are dietary Sources adequate to prevent disease? Lester Packer, PhD of the Department of Molecular and Cellular Biology at UC Berkeley, indicates vitamin E deficiency is rare in healthy adults, but vitamin E requirements vary fivefold between individuals depending upon their intake of polyunsaturated fats, tissue composition (fat), and steady supply of other interactive antioxidants.( 75) Thus consumption of vitamin E needs to be high enough to meet varying demands. High triglycerides appears to be a marker of high saturated and polyunsaturated fat intake.( 76) Thus high triglycerides may serve as one marker for increased need for vitamin E.

While the Recommended Daily intake of vitamin E ranges from 12-15 IU/day, supplementation with as little as 25 IU of vitamin E reduces oxidation (hardening) of LDL cholesterol within blood vessel walls and doses in the range of 400-800 IU provided optimal protection.( 77) Combined supplementation of 1 gram of vitamin C, 30 mg. of beta carotene and 800 IU of vitamin E/day resulted in a 40% reduction in oxidation of LDL cholesterol. Another group receiving 800 IU of vitamin E alone showed similar protection of LDL oxidation.( 78) Thus vitamin E may be the primary agent to prevent coronary artery disease. But this data must be interpreted in light of the fact high-dose vitamin E may reduce beta carotene levels and thus suppress beta carotene's effectiveness in preventing oxidation of LDL cholesterol.

A seemingly small increase of cholesterol (10%) is undesirable as this may significantly raise the risk of a cardiovascular event. However, when 600 IU of daily vitamin E is supplemented to women with mammary dysplasia (at risk for breast cancer), there is a significant rise ( 8-14%) in total cholesterol, though this is a result of a rise in protective HDL cholesterol and not in the atherogenic LDL cholesterol.( 79) With vitamin E supplementation there was a slight decrease in LDL in this study group. This is another example of dynamic factors which must be carefully assessed when administering supplemental fat-solubles.

The fact that high dose vitamin E is necessary to prevent fats from hardening (oxidizing) within blood vessel walls has to be interpreted within the context of a sedentary population of Americans who consume 36% of calories from fat. In Tanzania coronary heart disease is nearly nonexistent and vitamin E supplements are not necessary to accomplish that feat. Rural tribes of Tanzanians primarily consume plant foods, and only 0.2% exhibit two or more risk factors for coronary artery disease.( 80) Compare that figure with the United States where coronary artery disease accounts for about 36% of all deaths.( 81) Large-dose vitamin E may have greater application to those who consume a high-fat diet.

The antioxidant supplement manufacturers thrive in the shadow of processed food companies who spend millions of dollars to promote non-nutrient-dense fatty foods on television. Children are lured to eat fatty foods by celebrity clowns and once the taste of fatty foods has been acquired parents have great difficulty convincing their children that an apple, spinach or a carrot are tasty foods next to sugar-laden cereals, hamburgers, hot dogs and pizzas.

Recent studies suggest high-dose vitamin E (800 units) be supplemented among heart disease patients,( 82) which should cause physicians to review dietary and supplementary consumption of carotenoids among their cardiac patients taking vitamin E. Balance between these fat-soluble nutrients appears to be wise.

Cholesterol and Fat Soluble Antioxidants

Too much attention has been given to elevated cholesterol levels and their role in coronary artery disease and not enough on the importance of cholesterol as a carrier of antioxidants to tissues throughout the body. Since cholesterols (lipoproteins) carry fat-soluble antioxidants to tissues where they can be deposited, additional factors or drugs which increase or reduce cholesterol, or alter the fractions of cholesterol (HDL-high density lipoproteins), LDL-low density, VLDL-very low density, and triglycerides) may increase or decrease the risk for disease.

The body contains about 100-150 milligrams of carotenoids, with 80-85% stored in adipose tissue, 8-12% in the liver and about 1% in the circulation.( 85) It's cholesterol which provides the bus ride for fat-soluble antioxidants' travel to tissues. The chart below reveals how alteration of cholesterol profiles may affect carotenoid availability to the blood circulation and subsequently to tissues throughout the body.

Carotenoid and Cholesterol Profiles

Lipo

Total

Lyco

B

Lutein/

protein carotenoids

pene carotene zeaxanthin

VLDL

14

* 10
* 11

16

LDL

55

* 73
* 67

31

HDL

31

* 17
* 22

53

Source: Clevidence BA, Bieri JG, Association of carotenoids with human plasma lipoproteins, Methods Enzymology 1993; 214:33-38

Another study shows that lutein is carried almost evenly on LDL (44%) and HDL (38%) cholesterol.( 83) Vitamin E has no specific plasma transport protein and can travel on any of the lipid (cholesterol) molecules. However, vitamin E tends to travel on LDL particles in males and HDL particles in females. Vitamin E is preferentially delivered to the nervous system (retina, brain, peripheral nerves) on HDL particles.( 84)

M.K Horwitt and colleagues say "no one ever should report a serum tocopherol level without presenting simultaneous data on the total serum lipids." Horwitt notes, like carotenoids, the blood circulation contains only about 1% of the total body vitamin E. Thyroid hormones, high polyunsaturated fat diets and drugs (cholesterol-lowering) are factors which decrease blood lipids, while thyroid inhibitors, consumption of saturated fats and cholesterol may raise serum levels of vitamin E. As blood lipids increase so do levels of serum fat-solubles, such as vitamin A. Horwitt went as far as recommending that all future readings of vitamin E include side-by-side lipid levels. For example, serum vitamin E levels/total serum lipids = 0.62 mg./630 mg. in 100 milliliters of serum. Horwitt suggests that the ratio of lipid-soluble vitamins to total cholesterol is of importance and ratios >0.8 mg/gram represent normal vitamin E nutritional status in adults. Ratios less than 0.4 indicate true vi tamin E deficiency. Horwitt's suggestions were made in the prestigious Annals of the New York Academy of Sciences in 1972 and appear to have been ignored.( 85)

Should we raise or lower cholesterol? Dr. William Castelli, the director of the Framingham Heart Study, notes there are as many heart attacks in people with a total cholesterol under 200 mg/dl, a desirable cholesterol count, as occur in those with cholesterol over 300 mg/dl. Castelli suggests raising the HDL cholesterol. In other words, a total cholesterol of 239 with an HDL of 80 would be OK. An NIH panel suggests HDL be 35+ mg/dl and to accomplish that goal by low-fat diets, exercise, smoking cessation and weight loss rather than by drug therapy.( 86)

Cholesterol Reduction and Cancer

A dynamic exists between cholesterol, fat-soluble antioxidants and cancer. High intake of vitamin A or its precursor beta carotene may not result in decreased risk of cancer if cholesterol levels are low. Vitamin A travels on lipoproteins (cholesterol molecules), particularly low-density lipoproteins (LDL). Richard B. Shekelle and associates at the University of Texas School of Public Health in Houston found the risk of lung cancer was highest when the intake of beta carotene was restricted among those whose total serum cholesterol was low. Based upon data by Shekelle and other studies, lung cancer risk appears to be greater among adult males whose daily beta carotene intake is less than 3000 IU of vitamin A activity and whose serum cholesterol is less than 170 mg/dL.( 87)

Elevated cholesterol may also appear to increase the risk of cancer due to an accompanying increase in lipid peroxidation in fatty tissues. For example, elevated cholesterol has been associated

Elevated cholesterol may also appear to increase the risk of cancer due to an accompanying increase in lipid peroxidation in fatty tissues. For example, elevated cholesterol has been associated with an increased risk of developing ovarian cancer. As cholesterol levels increase so do vitamin E levels because of the increased lipoprotein particles available to transport vitamin E. The increased vitamin E is not a cause of ovarian cancer, but rather saturated fat which increases lipid peroxidation.( 88)

To repeat, the singular focus has been on reducing cardiovascular risk through modification of cholesterol profiles rather than gauging cholesterol's impact as a carrier of fat-soluble antioxidants in other disease states, particularly cancer. Serum vitamin E levels rise as cholesterol increases.( 89) Reducing cholesterol among individuals whose antioxidant consumption is low, among those with infectious disease and parasitic infections, and among the elderly and individuals with retinal disease, may not be wise in light of the facts presented in this report. Consultation with an informed physician is advised.

Data is accumulating which shows that low cholesterol is associated with increased mortality from cancer. A 17-year study of adults age 25-74 in New Zealand confirmed that low serum cholesterol may be associated With increased mortality rates from cancer.( 90) Among a population of nursing home residents, declining cholesterol (reduction >45mg/dL) increased the relative odds of dying by a factor of six. Greater than 20% reduction in cholesterol in a year increased the risk of dying by a factor of seven. Nine-percent of older (>65 years of age) hospitalized patients developed low cholesterol levels and most were patients who had developed infections or had undergone surgery.( 92) University of California researchers, using data extrapolated from rodents, suggest the avoidance of cholesterol-lowering drugs given increased rates of cancer among animal populations on these agents.( 93)

With 26 million prescriptions for cholesterol-lowering drugs in 1992 and over 8 million Americans on these medications, and the reports that modern medicine is losing the war against cancer,( 94) Consumer Reports was drawn to write a report on the growing concern over the use of these drugs over dietary and other measures to reduce cholesterol. Consider the sales of these drugs exceeds $400 million annually.

Readers who are searching for safer alternatives to cholesterol-lowering drugs may want to try garlic. Warshafsky and colleagues showed that a clove of garlic a day reduces serum cholesterol levels by about 9% which is equivalent on average to that of cholesterol-lowering drugs now being marketed.( 96) Another study shows that a clove of garlic a day for 26 weeks reduced serum cholesterol by 20% among 40-50 year old males and blood clotting thromboxane levels were also reduced by about 80%.( 97) Remarkably, garlic has been found to prevent an increase in cholesterol even when eating a meal with butter fat.( 98) Thus garlic can readily serve as a preferred alternative to cholesterol-lowering drugs as well as substitute for an aspirin a day to thin the blood and reduce the risk of heart attacks. Because cholesterol is important for the transport of antioxidants throughout the body, cholesterol reduction should be accompanied by increased intake of antioxidants. Garlic serves to reduc e cholesterol while boosting antioxidant protection by virtue of its selenium content (selenium + vitamin E = glutathione peroxidase).

Niacin is another effective nonprescription cholesterol-reducing agent. Like all agents that reduce cholesterol, high doses and prolonged use may cause problems. High-dose niacin (>3000 mg/day) may produce dry eyes and retinal problems. Reduction of cholesterol may thin the outer lipid layer of the tear film, resulting in dry eye problems. Cholesterol-lowering agents can interfere with normal levels of fatty acids in body tissues. No more than 1000 mg. of daily niacin is recommended.( 99)

Fat Blockers and Fat-Soluble Nutrients

A commercial fat-blocker that would assist overweight Americans in shedding pounds and reducing cholesterol is being pursued by a number of companies. Over one-half of U.S. adults choose reduced-fat versions of snack foods over the full-fat versions. People tend to eat more of a food when they know that it is reduced in fat.( 100) The most widely publicized fat blocker is Olestra(TM), Proctor & Gamble's 25-year, $200 million fat substitute, which will be incorporated into Pringles(TM) potato crisps and other snack foods.( 101) Because Olestra is indigestible it interferes with fat-soluble nutrient absorption. To make up for this potential problem P&G fortifies Olestra with fat-soluble vitamins but not carotenoids. Eating just 15 Olestra potato chips a day for 8 weeks reduces blood carotenoid levels by 50% and just six chips a day reduces beta carotene levels by 20%. While the FDA gave P&G the go-ahead to market this fat substitute in January 1996, the University of California Berk eley Wellness Letter was quick to give Olestra a thumbs-down vote.( 102) The American Academy of Ophthalmology's Research and Regulatory Agencies Committee urged caution in the approval of Olestra, which forced the FDA to require continued monitoring of the impact this product has on carotenoid levels.( 103) Olestra becomes only the fifth food ingredient to receive FDA approval that is not on the GRAS (Generally Regarded As Safe) list.

One of the simplest and most economical fat blockers available is activated charcoal. The British journal Lancet reports just a quarter-ounce of activated charcoal taken three times a day for four weeks reduces cholesterol by a whopping 41%. Consider that conventional drugs reduce cholesterol by 10-16%. HDL "good" cholesterol levels rose slightly on charcoal. What more, activated charcoal was effective among patients who had previously taken cholesterol-lowering drugs and had only moderate success.( 104)1 Activated charcoal is nontoxic and very inexpensive and even helps to reduce intestinal gas. There were no side effects in the study cited above, but the study lasted only four weeks. Long-term use of charcoal is likely to interfere with fat-soluble nutrient absorption. The most potent cholesterol-lowering agent and fat blocker of all time, activated charcoal, is widely available. But its daily use may pose the same problems as does Olestra and other fat-blocking agents.

Viruses and Parasites Interfere With Absorption and Transport of Fat Soluble Nutrients

A reduction in cholesterol, particularly HDL cholesterol, has been reported during a number of viral, parasitic or bacterial infections.( 105) It is well known that total serum cholesterol, and fractions of cholesterol (HDL, LDL and VLDL) may be temporarily altered during viral or bacterial infections or may emanate from stressful events (shock, burns, trauma, sepsis).( 106)

When chickens are infected with coccidia (E. acervulina), a parasite of the liver and intestinal tract, there is a marked reduction of xanthophyll carotenoids. The parasite is believed to interfere with intestinal absorption of the xanthophylls.( 107) Another study shows when chicks are infected with a parasite their mean plasma levels of lutein drop by an average of 71%,( 108) which would serve as an explanation for the visual problems associated with coccidiosis. The concentration of carotenoids in blood plasma is nearly cut in half when humans are infected with heliobacter pylori.

Human parasitic infections are common. Heliobacter pylori, a common intestinal bacterium which infects human populations,( 110) causes higher gastric Ph (less acid), more damage to the epithelial layer of the gastric tract, and lower levels of vitamin C in the gastric juice compared to non-infected individuals.( 111) Parasites or bacteria may set the stage for disease by interfering with fat absorption and altering cholesterol profiles, thus reducing transport and delivery of fat-soluble antioxidants to tissues.

In a study group of 485 healthy asymptomatic volunteers (age range 1580) in Houston, 52% were infected with Heliobacter pylori. The prevalence of this bacterium in blacks was twice that of whites (70% to 34%). The risk of Heliobacter pylori infection increases with age, about 1% per year in the population at large.( 112) H. pylori may tend to occur in family clusters which can cause investigators to falsely believe health problems emanating from this bacterium are caused by genetic factors. Among spouses of infected partners, 68% had H. pylori compared to only 9% of spouses of non-infected partners. Children are more likely to be infected if their parents are infected (40% vs. 3%).( 113)

Parasitic infections and malnutrition are highly prevalent in developing countries. Parasites like giardia often feed on or interfere with the absorption of nutrients such as vitamin B12, vitamin A, monosaccharides and disaccharides. Hookworm results in blood loss, loss of protein, trace elements and vitamin A, and impaired absorption of fats and sugars. Parasitic infections can reduce work productivity and energy in adults without apparent anemia. When malnourished individuals with parasitic infections are given supplemental nutrients, a flare up of the symptoms may occur.( 114)

Thus, it is plausible that nutrient-dense foods and nutritional supplements may actually exacerbate the problem by feeding the parasite. Immunosuppressed individuals, who are prone to opportunistic gut infections (e.g. HIV infected individuals), may require expert medical consultation regarding methods of eradicating intestinal parasites while avoiding wasting due to malabsorption, recognizing nutritional support may spur growth of the pathogen.

All chemotherapeutic agents used against parasitic infections have serious toxic side effects, including cardiac and/or renal failure. The most important naturally occurring anti-parasitic agent is berberine,( 115) a compound found in herbal plant extracts such as goldenseal, barberry, and Oregon grape. Berberine has been shown to be effective against intestinal parasites including giardia as well as showing antibiotic activity against candida (yeast overgrowth) and food-borne bacteria such as E. Coli and salmonella. Safe dosage is 250-500 milligrams of powdered dry extract (4:1 extract or 8-12% alkaloid content) for short periods of time (up to 2 weeks).( 116) Use of herbs containing berberine should be avoided during pregnancy as high doses may interfere with vitamin B metabolism. Berberine has been shown to increase the secretion of bile, which is required for the absorption of vitamin E. Increases in intracellular calcium are required for parasites to invade host cells and cal cium chelators (magnesium is a natural calcium blocker, or chelation therapy) may decrease parasitic counts in cells.( 117)

The Role of Estrogen in Maintaining Lipoprotein Fractions

It is widely known that estrogen appears to play a protective role in the body against vascular disease. Women have higher levels of HDL cholesterol, while males have higher levels of LDL and VLDL cholesterol. Individuals with marked HDL deficiency may have strikingly premature coronary artery disease.( 118) Postmenopausal women are 2-3 times more likely to have a heart attack than premenopausal women. This is attributed to the protective effect of increased HDL cholesterol among premenopausal women (progestins have no effect upon HDL). Estrogens work by increasing the synthesis of apolipoprotein A1 within HDL cholesterol while decreasing liver lipase secretion.( 119) Estrogen increases HDL cholesterol fractions in the blood circulation primarily by its ability to change lipase secretion. Only 30-50% of the protective cardiovascular effect of estrogens in women is attributable to elevation of HDL cholesterol, the remaining effect may be due to circulating fat-soluble antioxidant a ction.( 120) Thus postmenopausal women who don't replace estrogen may need to increase antioxidant intake to make up for reduced availability of transporting HDL cholesterol.

Among women over age 65, only 6.1% reported current use of estrogen replacement, and only 18.5% past use.( 121) In one study among older women age 60-72, hormone replacement therapy increased HDL (from 52 to 63 mg/Dl) and triglycerides (107 to 152 mg/Dl) while reducing LDL cholesterol (140 to 116 mg/Dl).( 122)

Do any untoward conditions emerge as a result of the decrease in HDL cholesterol in the postmenopausal years? An example is macular degeneration, which increases by a factor of five in postmenopausal women.( 123) This could be explained by the reduction of retinal lutein which depends upon cholesterol for transport from the liver to the retina.

Fat Malabsorption and Fatty Nutrients

Fat malabsorption problems frequently accompany gastrointestinal disease resulting in deficiencies of fatty acids and protective antioxidants which can contribute to systemic disease such as ulceration, nerve demyelinating diseases and immune disorders.( 124) Subjects with chronic pancreatitis may absorb xanthophylls more efficiently than carotenes.( 125) In one study, low levels of plasma tocopherol, below 0.225 mg/100 ml., were always preceded by at least nine months of a gastrointestinal disease. ( 126) In cases of fat malabsorption circulating levels of vitamin E are very low and either massive oral doses or intramuscular injection resolves the problem.( 127)

Among patients with partial gastrectomy, alcoholics and others with malabsorption problems, supplementation of vitamin E improves plasma vitamin E levels and reduces red blood cell destruction associated with vitamin E deficiency. Supplemental vitamin E appears to be indicated in cases of undernutrition or malabsorption.( 128) Problems of malabsorption can be overcome where it applies to vitamin E availability. Neurological and retinal damage caused by malabsorption of vitamin E from birth has been thwarted by oral administration of vitamin E.( 129-130)

Lipid peroxidation can lead to liver inflammation and poor bile flow, a problem which is countered by adequate supply of vitamin E.( 131-132) The administration of water-soluble vitamin E reverses neurologic problems associated with poor bile flow and liver disease.( 133) Water-soluble vitamin E has been given to children with liver disease and reversal of neurologic dysfunction observed.( 134) Patients with cystic fibrosis do not secrete pancreatic enzymes and bile and thus mal-absorb vitamin E.( 135) Among cystic fibrosis patients who have low circulating levels of vitamin E, the administration of oral water-soluble vitamin E restores blood levels to normal.( 136) Cystic fibrosis patients also may experience malabsorption of vitamin A which results in retinal dysfunction and night blindness. The oral administration of 25,000 IU/day of vitamin A resulted in normalization of the electroretinogram.( 137) (Encapsulated water-miscible forms-of vitamin A and E are available from J.R. Carl son Laboratories, Arlington Heights, Illinois. Other companies provide water-miscible forms of vitamin E as a nonencapsulated liquid.)

It has been shown that the effectiveness of herbal and vitamin supplements is dependent upon secretion of gastric juice (acid and pepsin). Secretion of digestive juice or the lack of the same may explain why certain individuals will derive benefits from free-radical scavenging agents while others exhibit no benefits. Digestion and absorption are important factors that may influence clinical trials of nutritional supplements.( 138)

Other Factors Involved in Fat-Soluble Antioxidant Metabolism

There are other factors, aside from cholesterol, liver function, estrogen, malabsorption, viruses and parasites, that affect the availability of fat-soluble nutrients. Among these are:

Inflammation: Acute inflammation is associated with changes in blood lipids, usually resulting in lowered cholesterol.( 139) Low serum concentrations of vitamin A may occur in cases of chronic infection and/or liver disease.( 140)

Lipase: A reduction in the liver enzyme lipase results in high triglycerides as well as elevated HDL and LDL cholesterol and is sometimes evidenced by premature corneal arcus (a fatty ring of cholesterol visible around the edge of the iris of the eye).( 141) Antibodies can alter the secretion of lipase, the liver enzyme responsible for fat metabolism, which can alter cholesterol profiles.( 142) It is interesting to note that Vannas and Orma in 1958 used heparin, which stimulates hepatic lipase, along with supplemental vitamin A and E, to resolve cases of macular degeneration.( 143)

Stress: The adrenal glands, located atop the kidneys, respond to emotional and physical stress by producing hormones such as acetylcholine that dilates blood vessels. All forms of stress have been shown to result in acute reduction of plasma triglyceride concentrations.( 144) Steroids, both endogenously produced by the adrenal gland, or given as a pharmaceutical agent, may alter HDL cholesterol profiles. Long-term use of steroid drugs apparently raises LDL cholesterol, while secretion of adrenal hormones elevates HDL in older adults (but not older diabetics).( 145) Stress, by its ability to alter adrenal hormone levels and cholesterol, may affect the delivery of fat-soluble antioxidants to tissues.

Sunlight And Carotenoids: Skin exposure to ultraviolet light significantly reduces plasma levels of carotenoids. The plasma vitamin A levels remain constant following repeated exposure to UV radiation, leading one to believe that the nonvitamin A carotenoids, xanthophylls (lutein, zeaxanthin) and lycopene, may be affected.( 146) One study shows the epidermal concentration of lycopene (the red carotenoid pigment found in tomatoes) is cut in half when exposed to UV light.( 147)

The fact that the retina is directly exposed to sunlight filtered only by the usually clear cornea, lens and vitreous, leaves it vulnerable to light exposure, specifically to the blue waveband of sunlight. Retinal lutein may be oxidized and obliterated from the central retina upon exposure to bright sunlight. Daily replenishment along with the use of blue-blocking sunglasses may be advisable.

Age As An Antioxidant Dynamic: Another dynamic factor is age. One study supports that with age the requirement for vitamin C and possibly beta-carotene increases while vitamin E is unchanged.( 148) Higher fat intake significantly increases the serum beta carotene levels of 18-30-year old men but not 65-80-year olds. It appears that old men have more difficulty in mobilizing beta carotene, indicative of possible competition from other micronutrients for passive absorption and/or transport on cholesterol fractions.( 149)

Exercise: A short-term exercise program among young sedentary women reduced plasma levels of all five carotenoids measured.( 150)

Alcohol: Moderate alcohol intake decreases particle number of LDL cholesterol upon which many fat-soluble nutrients ride, without changes in vitamin E content. Beta carotene is decreased significantly by even moderate alcohol intake.( 151) Healthy, nonsmoking, premenopausal women who consume 30 grams of alcohol per day were found to have significantly lower plasma levels of alpha and beta carotene, lycopene and vitamin E (lutein not tested). Alcohol has an independent lowering effect on plasma carotenoids.( 152) Another study shows that the combination of alcohol and beta carotene leads to more liver damage in animals than that produced by alcohol exposure alone.( 153)

Target Antioxidants

As mentioned previously, antioxidants may have an affinity for certain organs or tissues, making them more useful for certain health problems. These are called target antioxidants. Fat-soluble antioxidants, attached to a cholesterol molecule, travel through the blood circulation in very small concentrations and are deposited in certain tissues, held by binding proteins. Beta carotene is the major carotenoid in the liver, adrenal gland, kidney, ovary and fat, whereas lycopene is the predominant carotenoid in testes.( 154) This correlates with the finding that lycopene consumption from tomatoes is associated with a reduced risk for prostate cancer.( 155)

Combined Fat-Soluble Antioxidant Relationships And Disease

In a society where there is a phobia over cholesterol, where consumption of green leafy vegetables is low, where artificial fats are now being promoted, where diet books abound, and half of the public now takes nutritional supplements (many of which contain high-dose beta carotene), what kinds of diseases are likely to surface?

One "environmental" disease this reporter now associates with the above combined factors is macular degeneration. As documented earlier in this report, high-close beta carotene in supplements excludes the little bit of lutein in the common American diet from being absorbed. The low-fat diet or use of cholesterol-lowering drugs leads to reduced gastric absorption of all carotenoids and fat-soluble nutrients, leaving the central retina more vulnerable to damage caused by sunlight. A recent study showed that the dietary consumption of fat is directly related to increased retinal density of the yellow pigment lutein. High dietary intake of lutein-rich foods accompanied by a low-fat diet may still result in less than optimal levels of retinal lutein.( 156)

Macular degeneration is an eye disease which was virtually unknown in Japan 30 years ago. Today it is common there.( 157) After factoring for increased longevity in the population, researchers in Britain are completely stymied over what has caused a 30-40% increase in macular degeneration in the past 50 years.( 158) Yet in a remote community in Southern Italy the prevalence of macular degeneration is extremely low. Retinal aging spots called drusen were only found in 4.5% of rural Italians over 59 years of age. This is attributed to consumption of homegrown foods and the infrequent use of commercially processed foods.( 159) In a comparable population of elderly Americans the retinal drusen rate is 16-30%!( 160)

Summary

The current anxiety over the safety of beta carotene emanates from faulty research which often is too narrowly focused and does not utilize information which is widely available in the medical literature. In Denmark beta carotene supplements must now carry labels warning of potential health risks to smokers.(161) In retrospect, conducting a clinical trial with two fat-soluble nutrients which compete with each other for absorption appears to be a major flaw. The competition between vitamin A and E has been well documented in the medical literature since the 1940's.(162-163) Another flaw is the attempt to throw a pill at what is a lifestyle disease. A third flaw is throwing two fat-soluble nutrients at a disease when a majority of the participants in the study consumed high amounts of alcohol and are likely to have impaired liver function. A fourth flaw is the absence of a water-soluble antioxidant such as vitamin C which is known to be in short supply among smokers.(164,165) A re cent study points to natural beta carotene ( 9-cis) as being a more efficient antioxidant than synthetic (all-trans) beta carotene in human serum. Synthetic beta carotene was used in several beta carotene/cancer prevention studies. Researchers suggest more attention to the stereoisomeric configuration and mode of intake of carotenoids rather than just dosage.(166) The major oversight is the absence of lutein which has been shown in epidemiological studies to reduce the risk of lung cancer among smokers.

In a study of 282 elderly subjects, plasma vitamin E and beta carotene levels were significantly influenced by alcohol and cigarette consumption as well as plasma lipid levels.(167) Epidemiologists remark that "incomplete control of these factors could lead to false estimates of increased cancer risk."(168)

The advice to consume fruits and vegetables goes unquestioned but still remains vague. According to the citations in this report, smokers should be specifically advised to increase consumption of kale, spinach, amaranth, paprika, collard and mustard greens, all of which are rich sources of lutein. The daily consumption of xanthophylls should exceed that of carotenes. Since it would require the ingestion of 33 cups of spinach a day to equal the xanthophyll intake of Fiji Islanders who smoke yet exhibit low rates of lung cancer, the provision of supplements is more practical. Smokers also require replenishment of vitamin C, vitamin E, and bioflavonoids.

The term "mixed carotenoids" is loosely used. Mixed carotenoids should be comprised of lutein and beta carotene with other carotenoids like lycopene. Unfortunately bulk mixed carotenoids provide beta carotene in a 100:1 ratio over lutein.(169) A purified form of lutein needs to be added to equalize purified beta carotene.

Helenien is an esterified marigold product which is being substituted for lutein in various nutritional supplements. Helenien does not provide the free lutein consumed from foods like spinach. Helenien is less bioavailable than free lutein. Extracts of marigold meal have been shown to contain a natural insect repellant component of the marigold flower petal(170) and other undesirable chemicals. Lutein from raw marigold petals is not a very utilizable form of xanthophyll pigment.(171) Kemin Foods (Des Moines, Iowa) provides their Flora-Glo(TM) lutein product in a base of vegetable oil (safflower oil) to enhance absorption and then stabilize it by adding vitamin E, rosemary and citric acid.(172) Supplements containing helenien should be accurately labelled as "helenien" and not free lute in.

Mixed forms of vitamin E (alpha, beta, gamma, delta tocopherols) cannot be equated to mixed forms of carotenoids. Some supplement manufacturers label their products as "vitamin E plus mixed tocopherols," but the "mixed" portion is variable, often less than 1% (<.2 mg.) of the product. Where clinicians believe mixed tocopherols are potentially beneficial to their patients (i.e. smokers, cardiovascular disease), a formula is available which provides alpha tocopherol with a significant amount of beta, delta, gamma tocopherols. Carlson Laboratories EGEMS PLUS provides alpha tocopherol in 200, 400 or 800 IU gelatin capsules with a significant amount of non-alpha tocopherols ( 34, 67,and 134 mg. of non-alpha tocopherols respectively).(173)

Natural forms of vitamin E (d-alpha tocopherol, also referred to as RRR-alpha tocopherol) appear to be advantageous over synthetic forms (d-alpha tocopherol). In an animal study, Ingold has shown that the naturally-occurring form of vitamin E (called RRR) accumulates in plasma, erythrocytes and the brain rather than the synthetic form (SRR). The natural form of vitamin E is more potent than synthetic forms.(174) The US Pharmacopoeia lists synthetic vitamin E as 26% less potent than natural vitamin E.(175) Based upon fat resorption assay, RRR-alpha-tocopheryl acetate (natural vitamin E) has been shown to be 36% more biologically active than all-rac-alpha-tocopheryl acetate (synthetic vitamin E) in rodents. However, in humans researchers indicate natural vitamin E "is almost twice as bioavailable as synthetic vitamin E."(176) Similarly, some vitamin E supplements are labelled as "natural vitamin E," though the percentage of natural vitamin E (d-alpha tocopherol) may be no more tha n 5% of the total. It is unlikely that consumers will be able to sort out these differences in nutritional supplements. Clinicians may need to instruct their patients to rely on reputable companies who provide accurate labelling of their vitamin E products and only use 100% natural vitamin E.

Use of more bioavailable forms of vitamin E and carotenoids are likely to be clinically significant for many individuals who have fat malabsorption problems (Heliobacter pylori?), who smoke tobacco, whose liver function is compromised, or who have diminished transport mechanisms (altered lipoproteins) for delivery of fat-soluble nutrients to tissues. More than half of the patients with chronic congestive heart failure have been found to have fat malabsorption problems.(177)

While the information in this report provides greater understanding of factors involved in disease prevention and health maintenance, there is still no promise that pre-cancerous states or overt lung tumors can be reversed as long as individuals continue to smoke and consume excessive amounts of alcohol. Attempts to apply this information may require the skill of health professionals and nutritionists who understand the difference between nutrition for optimal health maintenance among healthy individuals, and therapeutic nutrition which attempts to reverse disease states among those who are ill.

Because humans in developed countries are higher in the food chain and live in environments with good sanitation does not mean they are invulnerable to unfriendly intestinal bacteria. Veterinarians customarily examine all animals for parasites and these pathogens are assumed to be present in herds of animals who are periodically prescribed anti-parasitic agents in their feed. The often unrecognized but widespread prevalence of parasitic infection suggests the public become more aware of natural remedies which are known to be hostile to these pathogens.

Correspondence:

Bill Sardi

Health Spectrum Publishers, Inc.

8851 Central Avenue, G-620

Montclair, California 91763 USA

909-982-2953/Fax 909-949-3801
References:

(1.) London SJ, et al, Carotenoids, retinol, and vitamin E risk of proliferative benign breast disease and breast cancer, Cancer Causes and Control 1992: 3: 503-12.

(2.) Block G, Patterson B, Subar A, Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence, Nutr Cancer 1992; 18: 1-29.

(3.) The alpha tocopherol, beta carotene, cancer prevention study group, The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers, The New England Journal Medicine 1994; 330: 1029-35.

(4.) Finnish beta carotene study considered seriously flawed, Natural Foods Merchandiser, June 1994, pp. 11-12.

(5.) Industry responds to beta carotene study, Health Supplement Retailer, March 1996, p. 42.

(6.) Stahl W, Schwarz W, Sundquist Ar, Sies H, cis-trans Isomers of lycopene and b-carotene in human serum and tissues, Arch Biochem Biophys 1992; 294: 173-77.

(7.) Esterbauer H, et al, The role of vitamin E and carotenoids in preventing oxidation of low density lipoproteins, Ann NY Aca Sci 1989; 570: 254-67.

(8.) Ziegler RG, A review of epidemiologic evidence that carotenoids reduce the risk of cancer, J Nut 1989; 119: 116-22.

(9.) Colditz GA, et al, Increased green and yellow vegetable intake and lowered cancer deaths in an elderly population, Am J Clin Nut 1985; 41: 32-36.

(10.) Grubbs CJ, et al, Effect of canthaxanthin on chemically induced mammary carcinogenesis, Oncology 1991; 48: 239-45.

(11.) Colacchio TA, Memoli VA, Hildebrandt L, Antioxidants vs Carotenoids, Archives Surgery 1989; 124: 217-21.

(12.) Mathews-Roth MM, Antitumor activity of b-carotene, canthaxanthin and phytoene, Oncology 1982; 39: 3337.

(13.) Schweitzer D, et al, Spectrometric investigations in ocular hypertension and early stages of primary open angle glaucoma and of low-tension glaucoma -- multisubstance analysis, Int Oph 1992; 16: 251-57.

(14.) Malinow MR, et al, Diet-related macular anomalies in monkeys, Invest. Ophthalmology 1980: 19:857-63

(15.) Kohlmeier L, Hastings SB, Epidemiologic evidence of a role of carotenoids in cardiovascular disease prevention, Am J Clin Nut 1995; 62: 1370S-76S.

(16.) Weiser H, Kormann AW, Provitamin A activities and physiological functions of carotenoids in animals, in Carotenoids in Human Health, Annals New York Academy Sciences 1993; 691: 213-15.

(17.) Zhang LH, Cooney RV, Bertram JS, Carcinogenesis 1991; 12: 2109-14.

(18.) Packer L, Carotenoids, Part A, Chemistry, separation, quantitation, and antioxidation, Methods in Enzymology 1992; 213: 151.

(19.) Dimitrov NV, Ullrey DE, Bioavailability of carotenoids, Carotenoids: Chemistry and Biology, NI Krinsky, et al, editor, Plenum Press, New York, 1990, pp. 269-77.

(20.) Roels OA, et al, Carotene balances in boys in Ruanda where vitamin A deficiency is prevalent, J Nutrition 1958; 65: 115-27.

(21.) Diplock AT, Safety of antioxidant vitamins and b-carotene, Am J Clin Nut 1995; 62: 1510S-16S

(22.) Krebs-Smith S, et al, US Adults' fruit and vegetable intakes, 1989 to 1991: a revised baseline for the Healthy People 2000 objective, Am J Pub Health 1995; 85:1623-29.

(23.) Russell RM, Gastrointestinal function and aging, in Geriatric Nutrition, John E. Morley, editor, Raven Press, Ltd., NY, 1990, pp. 231-37

(24.) Bednar C, Recorded food preferences of institutionalized elderly, FASEB Journal, February 28, 1992; 6: A1673, Abstract 4268.

(25.) Industry, FDA react to recent vitamin A study, Nutrition Science News, December 1995, p. 8.

(26.) Rothman KJ, et al, Teratogenicity of high vitamin A intake, The New England Journal of Medicine November 23 1995; 333: 1369-73.

(27.) Tanouye E, FDA clears first of new cancer drugs, The Wall Street Journal, November 29, 1995.

(28.) Kowalski TE, et al, Vitamin A hepatoxicity: a cautionary note regarding 25,000 IU supplements, Am J Med 1994; 97: 523-28.

(29.) Bendich A, Langseth L, Safety of vitamin A, Am J Clin Nut, 1989; 49:358-71

(30.) Holmes JA, Williams TD, Visual field changes related to Accutane treatment, Revue Canadian Ophthalmology 1994; 56: 99-102.

(31.) Willett WC, Hunter DJ, Vitamin A and cancers of the breast, large bowel, and prostate: epidemiologic evidence, Nutrition Reviews 1994; 52: S53-S59.

(32.) Fotouhi N, et al, Carotenoid and tocopherol concentrations in plasma, peripheral blood mononuclear cells, and red blood cells after long-term b-carotene supplementation in men, Am J Clin Nut 1996; 63: 553-58.

(33.) Bendich A, Olson JA, Biological actions of carotenoids, FASEB Journal 1989; 3: 1927-32.

(34.) Stacewicz-Sapuntzakis, et al, Serum reference values for lutein and zeaxanthin using a rapid separation technique, in Carotenoids in Human Health, Ann NY Acad Sci 1993; 691: 207-09.

(35.) Yao LL, Burri BJ, Furr HC, Carotenoid distribution among human plasma lipoproteins during dietary depletion, FASEB Journal, March 9, 1995, 9: A459, Abstract 2654.

(36.) Blomstrand R, Werner B, Studies on intestinal absorption of radioactive b-carotene and vitamin A in man. Conversion of b-carotene to vitamin A, Scandanavian J Clin Lab Invest 1967; 19: 339.

(37.) Underwood BA, et al, Liver stores of vitamin A in a normal population dying suddenly or rapidly from unnatural causes in New York City, Am J Clin Nut 1970; 23: 1037-42.

(38.) Kotulak R, Heart research buoys vitamin E, Chicago Tribune March 22, 1996.

(39.) Tangney CC, et al, Intra- and interindividual variation in measurements of b-carotene, retinol, and tocopherols in diet and plasma, Am J Clin Nut 1987; 45: 764-69.

(40.) Krinsky NI, Cornwell DG, Oncley JL, Archives of Biochemistry and Biophysics 1958; 73: 233-46.

(41.) Bowen PE, et al, Variability of serum carotenoids in response to controlled diets containing six servings of fruits and vegetables per day, in Carotenoids and Human Health, NY Academy Sciences 1993; 691: 24143.

(42.) Blakely SR, et al, Bioavailability of carotenoids in tomato paste and dried spinach and their interactions with canthaxanthin, FASEB Journal, March 15, 1994; 8: A192, Abstract 1108.

(43.) Reich P, Schwachman H, Craig JM, Lycopenemia, The New England Journal Medicine February 11, 1960; 262: 263-69.

(44.) Carughi A, Hooper F, Plasma carotenoid levels before and after supplementation with a carotenoid complex, in Carotenoids in Human Health, NY Academy Sciences 1993; 691: 244-45.

(45.) Micozzi MS, et al, Plasma carotenoid response to chronic intake of selected foods and b-carotene supplements in men, Am J Clin Nut 1992; 55: 112025.

(46.) Gaziano JM, et al, Discrimination in absorption or transport of b-carotene isomers after oral supplementation with either all-trans- or 9-cis-b-carotene, Amer J Clin Nut 1995; 61: 1248-52.

(47.) de Pee S, et al, Lack of improvement in vitamin A status with increased consumption of dark-green leafy vegetables, Lancet 1995; 346: 75-81.

(48.) Ascherio A, et al, Correlations of vitamin A and E intakes with the plasma concentrations of carotenoids and tocopherols among American men and women, J Nutrition 1992; 122: 1792-1801.

(49.) Le Marchand L, et al, An ecological study of diet and lung cancer in the South Pacific, International Journal Cancer 1995; 63: 18-23.

(50.) Ross MA, et al, Plasma concentrations of carotenoids and antioxidant vitamins in Scottish males: influences of smoking, Eur J Clin Nut 1995; 49:861-65.

(51.) Rimm E, Colditz G, Smoking, alcohol, and plasma levels of carotenes and vitamin E, Ann NY Acad Med 1993; 686: 323-34.

(52.) Stryker WS, et al, The relation of diet, cigarette smoking, and alcohol consumption to plasma beta carotene and alpha tocopherol levels, Am J Epid 1988; 127: 283-96.

(53.) Rimm E, Colditz G, Smoking, alcohol and plasma levels of carotenes and vitamin E, Ann NY Acad Sci, 1993; 686: 323-33.

(54.) Handelman GJ, Packer L, Crose CE, Destruction of tocopherols, carotenoids, and retinol in human plasma by cigarette smoke, Am J Clin Nut 1996; 63: 559-65.

(55.) Hammond BR Jr, Wooten BR, Snodderly DM, Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration, Vision Research, in press.

(56.) Paetkau ME, et al, Senile disciform macular degeneration and smoking, Canadian Journal Ophthalmology 1978; 13 67-71.

(57.) Brown AJ, Acute effects of smoking cessation on antioxidant status, J Nutr Biochem 1996; 7: 29-39.

(58.) Handelman GJ, et al, Oral a-tocopherol supplements decrease plasma y-tocopherol levels in humans, Journal Nutrition 1985; 115: 807-13.

(59.) Bieri JG, Evarts RP, Gamma tocopherol: metabolism, biological activity and significance in human vitamin E nutrition, American Journal Clinical Nutrition 1974; 27: 980-86.

(60.) Kitabchi AE, Wimalasena J, Specific binding sites for d-a-tocopherol on human erythrocytes, Biochimica et Biophysica Acta 1982; 684: 200-06.

(61.) Traber MG, Kayden HJ, Preferential incorporation of a-tocopherol vs. y-tocopherol in human lipoproteins, Am J Clin Nut 1989; 49: 517-26.

(62.) Handelman GJ, et al, Oral a-tocopherol supplements decrease plasma y-tocopherol levels in humans, J Nutrition 1985; 115: 807-13.

(63.) Wynder EL Taioli E, Fjuita Y, Ecologic study of lung cancer risk factors in the US and Japan with special reference to smoking and diet, Japanese J Cancer Res 1992; 83: 418-23.

(64.) Arnrich L, Arthur VA, Interactions of fat-soluble vitamins in hypervitaminoses, NY Acad Sciences 1980; 355: 109-18.

(65.) Dimitrov NV, et al, Bioavailability of b-carotene in humans, Am J Clin Nut 1988; 48: 298-304.

(66.) Weber U, et al, Carotenoid retinopathy, Klin Mbl Augenheilk 1985; 186: 351-54.

(67.) Hammond BR Jr, Iris color and macular pigment optical density, Experimental Eye Research, in press, 1996.

(68.) Seddon JM, et al, Dietary carotenoids, vitamins A, C and E, and advanced age-related macular degeneration, J Am Med Assoc 1994; 272: 1413-20.

(69.) Hankinson SE, et al, Nutrient intake and cataract extraction in women: a prospective study, British Medical Journal 1992; 305: 335-39.

(70.) Berson EL, et al, A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa, Archives Ophthalmology 1993; 111: 761-72.

(71.) Study shows vitamin A slows RP, National Retinitis Pigmentosa Foundation, Inc., Baltimore, MD, monograph 1993.

(72.) Willett WC, et al, Vitamins A, E, and carotene: effects of supplementation on their plasma levels, Am J Clin Nut 1983; 38: 559-66.

(73.) Blakely SR, et al, Effects of beta-carotene and related carotenoids on vitamin E, in Vitamin E in Health and Disease, L Packer, J Fuchs, editors, M Dekker, New York, 1993, pp. 63-67

(74.) Carotenoids, Encyclopaedia of food science food technology and nutrition, Volume I, Macrea R, et al, editors, Academic Prose, New York, 1993, pp. 707-13.

(75.) Packer L, Interactions among antioxidants in health and disease: vitamin E and its redox cycle, PSEBM 1992; 200: 271-75.

(76.) Nikkan T, et al, Fatty acid composition of serum lipid fractions in relation to gender and quality of dietary fat, Ann Med 1995; 27: 491-98.

(77.) Princen HMG, et al, Supplementation with low doses of vitamin E protects LDL from lipid peroxidation in men and women, Arterioscler Thromb Vasc Biol 1995; 15: 325-33.

(78.) Jialal I, Grundy SM, Effect of combined supplementation with a-tocopherol, ascorbate, and beta carotene on low-density lipoprotein oxidation, Circulation 1993; 88: 2780-86.

(79.) Sundaram GS, et al, a-tocopherol and serum lipoproteins, 1981; 16: 223-27.

(80.) Swai ABM, et al, Low prevalence of risk factors for coronary heart disease in rural Tanzania, International Journal Epidemiology 1993; 22: 651-59.

(81.) Gerster H, Potential role of beta-carotene in the prevention of cardiovascular disease, Int. J Vit Nut Res 1991; 61: 277-91.

(82.) Stephens NG, et al, Randomized controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS), The Lancet March 23 1996; 347: 781-86.

(83.) Romanchik J, et al, Transport of carotenoids and a-tocopherol in human plasma lipoproteins, FASEB Journal, March 15, 1994; 8: A192, Abstract 1111.

(84.) Traber ME, Cohn W, Muller DPR, Absorption, transport and delivery to tissues, in Vitamin E in Health and Disease, L Packer, J Fuchs, editors, M Dekker, New York, 1993.

(85.) Horwitt MK, Harvey CC, Dahm CH, Searcy MT, Relationship between tocopherol and serum lipid levels for determination of nutritional adequacy, Annals NY Acad Sci 1972; 203: 223-36.

(86.) Yulsman T, An NIH panel reaches a consensus on HDL screening for healthy Americans, Medical World News, March 1992, pp. 27-31.

(87.) Shekelle RB, et al, Serum cholesterol, beta carotene, and risk of lung cancer, Epidemiology 1992; 3: 282-87.

(88.) Helzlsouer KJ, et al, Prospective study of serum micronutrients and ovarian cancer, J Natl Cancer Inst 1996; 88: 32-37.

(89.) Konneh MK, et al, Tissue distribution of a-tocopherol following dietary supplementation in the rat: effects of concomitant cholesterol feeding, Proc Soc Exp Biol Med 1995; 210: 156-61.

(90.) Salmond CE, et al, Are low cholesterol values associated with excess mortality? British Medical Journal 1985; 290: 422-24.

(91.) Grant MD, et al, Declining cholesterol and mortality in a sample of older nursing home residents, J Am Ger Soc 1996; 44: 31-36.

(92.) Noel MA, et al, Characteristics and outcomes of hospitalized older patients who develop hypocholesterolemia, J Am Ger Soc 1991; 39: 455-61.

(93.) Newman TB, Hulley SB, Carcinogencity of lipid-lowering drugs, J Am Med Assoc 1996; 275; 55-60.

(94.) Kolata G, Cancer progress data challenged, Science 1986; 230: 15-16.

(95.) The cholesterol question, Consumer Reports March 1996, pp. 36-37.

(96.) Warshafsky S, Kamer RS, Sivak SL, Effect of garlic on total serum cholesterol: a mta-analysis, Ann Intern Med 1993; 119: 599-605.

(97.) Ali M, Thomson M, Consumption of a garlic clove a day could be beneficial in preventing thrombosis, Prostaglandins Leukotrienes and Essential Fatty Acids, 1995; 53: 211-12.

(98.) Sharma KK, et al, Effect of raw and boiled garlic on blood cholesterol in butter fat lipaemia, The Indian Journal Nutr. Dietet. 1976; 13: 7: 7-10.

(99.) Fraunfelder FW, et al, Adverse ocular effects associated with niacin therapy, British Journal Ophthalmology 1995; 79: 54-56.

(100.) Miller GD, Groziak SM, Impact of fat substitutes on fat intake, Lipids 1998: 31: S293-96.

(101.) Giese J, Olestra: properties, regulatory concerns and applications, Food Technology, March 1996, p. 130-31.

(102.) Olestra: just say no, University of California Berkeley Wellness Letter 1996; 12: 1-2.

(103.) FDA jury out on Olestra, Argus,American Academy of Ophthalmology, March 1996, p. 18.

(104.) Kuusisto P, t al, Effect of activated charcoal on hypercholesterolaemia, The Lancet, August 16, 1986, p. 366-67.

(105,) Beisel WR, Fisher RH, Lipid metabolism during infectious illness, Am J Clin Nut 1970; 23: 1069-79.

(106.) Sammalkorpi K, et al, Changes in serum lipoprotein pattern induced by acute infections, Metabolism 1988; 37: 859-65.

(107.) Ruff MD, Fuller HL, Some mechanisms of reduction of carotenoid levels in chickens infected with Eimeria acervulina or E. tennella, J Nutrition 1975; 105: 144756.

(108.) Allen PC, Effect of coccidiosis on the distribution of dietary lutein in the chick, Poultry Science 1992; 71: 1457-63.

(109.) Drake IM, et al, Plasma antioxidant concentrations in Heliobacter pylori, Gastroenterology 1995; 108: Abstracts

(110.) Blaser MJ, The bacteria behind ulcers, Scientific American 1996; February pp. 104-07.

(111.) Rood JC, et al, Heliobacter pylori-associated gastritis and the ascorbic acid concentration in gastric juice, Nutrition Cancer 1994; 22: 65-72.

(112.) Graham DY, et al, Epidemiology of Heliobacter pylori in an asymptomatic population in the US, Gastroenterology 1991; 100: 1495-1501.

(113.) Malaty HM, et al, Transmission of Heliobacter pylori infection, Scandanavian J. Gastroenterology 1991; 26: 927-32.

(114.) Shetty PS, Shetty N, Parasitic infection and chronic energy deficiency in adults, Parasitology 1993; 107: S159-S167.

(115.) Iwu MM, Jackson JE, Schuster BG, Medicinal plants in the fight against Leishmaniasis, Parasitology Today 1994; 10: 65-68.

(116.) Murray MT, The Healing Power of Herbs, 2nd edition, Prima Publishing, 1995, p. 162-72.

(117.) Docampo R, Moreno SNJ, The role of Ca2+ in the process of cell invasion by intracellular parasites, Parasitology Today 1996; 12: 61-65.

(118.) Schaefer EJ, et al, The effects of estrogen administration on plasma lipoprotein metabolism in premenopausal females, J Clin Endocrin Metab 1983: 57: 262-67.

(119.) Tikkanen MJ, et al, High density lipoprotein-2 and hepatic lipase: reciprocal changes produced by estrogen and norgestrel, J Clin Endocrinol Metab 1982; 54:1113-17.

(120.) Bruckert E, Turpin G, Estrogens and progestins in postmenopausal women: influence on lipid parameters and cardiovascular risk, Hormone Res 1995; 43: 10003.

(121.) Hands VL, et al, Do older women use estrogen replacement? Data from the Duke established populations for epidemiologic studies of the elderly, J Am Ger Soc 1996; 44: 1-6.

(122.) Binder EF, Birge SJ, Kohrt WM, Effects of endurance exercise and hormone replacement therapy on serum lipids in older women, Journal Am Ger Soc 1996; 44: 231-36.

(123.) Klaver CCW, et al, Age-related maculopathy: a genetic-epidemiological approach, International Ophthalmology 1995; 19: 19.

(124.) Siguel EN, Lerman RH, Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders, Metabolism 1996; 45: 12-23.

(125.) Borel P, et al, Carotenoids in biological emulsions: solubility, surface-to-core distribution and release from lipid droplets, J Lipid Res 1996; 37: 250-61.

(126.) Goransson G, et al, Low plasma tocopherol levels in patients with gastrointestinal disorders, Scandanavian J Gastro 1973; 8: 21-23.

(127.) Vitamin E deficiency diseases and nutrient interrelationships, The Role of Fats in Human Nutrition, 2nd edition, AJ Vergroesen, M Crawford, editors, Academic Press, New York, 1989, pp. 375-82.

(128.) Losowsky MS, Leonard PJ, Evidence of vitamin E deficiency in patients with malabsorption or alcoholism and the effects of therapy, Gut 1967; 8: 539-43.

(129.) Kayden HJ, Traber MG, Clinical, nutritional and biochemical consequences of apolipoprotein B deficiency, Lipoprotein Deficiency Syndromes, A Angel and J Frohlich, editors, Plenum Press, New York, 1986, pp. 67-81.

(130.) Muller DPR, Lloyd JK, Wolff OH, Vitamin E and neurological function: abetalipoproteinemia and other disorders of fat absorption, in Biology of Vitamin E, CIBA Foundation Symposium 101, Pitman, London 1983, pp. 106-21.

(131.) Parola M, et al, On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis, Free Radical Biology & Medicine 1996; 20: 351-59.

(132.) Sokol RJ, et al, Mechanism causing vitamin E deficiency during chronic childhood cholestasis, Gastroenterology 1983; 85: 1172-82.

(133.) Sokol RJ, et al, Multicenter trail of d-a-tocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with chronic cholestasis, Gastroenterology 1993; 104: 1727-35.

(134.) Traber MG, et al, Uptake of intact TPGS, a water miscible form of vitamin E by human cells in vitro,Am J Clin Nut 1988; 48: 605-11.

(135.) Kayden HJ, Traber MG, Absorption, lipoprotein transport and regulation of plasma concentrations of vitamin E in humans, Journal Lipid Res 1993; 34: 34358.

(136.) Sung JH, et al, Axonal dystrophy in the gracile nucleus in congenital biliary atresia and cystic fibrosis: beneficial effect of vitamin E therapy, J. Neuropath & Exp Neurol 1980; 39: 584-97.

(137.) Leguire LE, et al, Electrooculogram in vitamin A deficiency associated with cystic fibrosis, Ophthalmic Paediatrics 1992; 13: 187-89.

(138.) Niwa Y, et al, Why are natural plant medicinal products effective in some patients and not in others with the stone disease? Planta Medica 1991; 57: 299-304.

(139.) Ettinger WH, et al, Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin: cholesterol acyltransferase in cynomolgus monkeys, J Lipid Res 1990; 31: 1099-1107.

(140.) Ralli EP, et al, Vitamin A and beta carotene content of human liver in normal and in diseased subjects, Archives of Internal Med 1941; 68: 102.

(141.) Little JA, Connelly PW, Familial hepatic lipase deficiency, Lipoprotein Deficiency Syndromes, A Anglel, J Frohlich, editors, Plenum Press, New York, 1986, pp. 253;60.

(142.) Jansen H, et al, On the metabolic function of heparin-releasable liver lipase, Biochemical and Biophysical Res Comm 1980; 92: 53-59.

(143.) Vannas S, Orma H, Acta Ophthalmologica 1958; 36: 601-12.

(144.) Chait A, et al, Reduction of plasma triglyceride concentration by acute stress in man, Metabolism, 1979; 28: 553-61.

(145.) Varma VK, et al, High density lipoprotein cholesterol is associated with serum cortisol in older people, J Am Ger Soc 1995; 43: 1345-49.

(146.) White WS, et al, Ultraviolet light-induced reductions in plasma carotenoid levels, Am J Clin Nut 1988; 47: 879-83.

(147.) Ribaya-Mercado JD, et al, Effects of B-carotene supplementation and ultraviolet (UV)- light exposure on serum and akin levels of carotenoids and retinoids, FASEB Journal, February 28, 1992; 6: A1646, Abstract 4111.

(148.) Heseker H, Schneider R, Requirement and supply of vitamin C, E, and beta-carotene for elderly men and women, Eur J Clin Nut 1994; 48: 118-27.

(149.) Shiau A, et al, Effects of diet on absorption of beta carotene in young and elderly subjects, FASEB Journal February 28, 1992; 6: A1646, Abstract 4109.

(150.) Kirkiles NC, et al, Short-term exercise training effects on plasma carotenoid levels in women, FASEB Journal, February 28, 1992; 6: A1646, Abstract 4112.

(151.) Suzukawa M, et al, Effects of alcohol consumption on antioxidant content and susceptibility of low-density lipoprotein to oxidative modification, Journal Am College Nutrition 1994; 13: 237-42.

(152.) Morman MR, et al, The effect of alcohol intake on plasma carotenoid levels: a controlled diet study, FASEB Journal, March 15, 1994; 8: A193, Abstract 1119.

(153.) Leo MA, Interaction of ethanol with b-carotene: delayed blood clearance and enhanced hepatotoxicity, Hepatology 1992; 15: 883-91.

(154.) Sies H, Vitamins E and C, b-carotene and other carotenoids as antioxidants, Am J Clin Nut 1995; 62: 13158-21S.

(155.) Giovannucci E, et al, Intake of carotenoids and retinol in relation to risk of prostate cancer, Journal Natl Cancer Institute 1995; 87: 1767-76.

(156.) Hammond BR Jr, Fuld K, Curran-Celentano J, Macular pigment density in monozygotic twins, Investigative Ophthalmology 1995; 36: 2531-41.

(157.) Bird A, Age-related macular disease, British Journal Ophthalmology 1996; 80: 2-3.

(158.) Evans J, Wormald R, Is the incidence of registrable age-related macular degeneration increasing? British Journal Ophthalmology 1996; 80: 9-14.

(159.) Pagliarini S, et al, Age-related maculopathy (ARM) in remote Southern Italy, Investigative Ophthalmology 1996; 37: ARVO Abstract 1917.

(160.) Klein R, Klein BEK, Linton KLP, Prevalence of age-related maculopathy, Ophthalmology 1992; 99: 933-43.

*Reporter's note: RP patients are known to be hypercholesterolemic and need more vitamin E. The retinal photoreceptors among RP patients are in need of omega-3 fatty acids. Vitamin E is critical for protection of lipid membranes in the retina. If readers have RP they may want to consult with a knowledgeable eye physician about separating their consumption of vitamin E away from vitamin A, i.e. at a different meal time.

(161.) Beta carotene, vitamin C censored by European governments, Natural Food Merchandisers Nutrition Science News 1996; 1: 4.

(162.) Johnson RM, Baumann CA, The effect of a-tocopherol on the utilization of carotene by the rat, J Biol Chemistry 1948; 175: 811-16.

(163.) Hebert JW, Morgan AF, The influence of alpha-tocopherol upon the utilization of carotene and vitamin A, J Nutrition 1953; 50: 175-90.

(164.) Pelletier O, Vitamin C status of cigarette smokers and nonsmokers, Am J Clin Nut 1970; 23: 520-24.

(165.) Pelletier O, Vitamin C and cigarette smokers, Ann NY Acad Sci 191975; 258: 156-67.

(166.) Ben-Amotz A, Levy Y, Bioavailability of a natural isomer mixture compared with synthetic all-trans b-carotene in human serum, Am J Clinical Nutrition 1996; 63; 729-34.

(167.) Herbeth b, et al, Determinants of plasma retinol, beta carotene, and alpha tocopherol, American Journal Epidemiology 1990;132: 394-96.

(168.) Stryker WS, et al, The relation of diet, cigarette smoking and alcohol consumption to plasma beta carotene and alpha tocopherol levels, Am. J. Epidemiology 1988; 127: 28.

(169.) Data, Henkel, La Grange, Illinois.

(170.) Weaver DK, et al, Insecticidal activity of floral, foliar, and root extracts of Tagetes minuta (Asterales: Asteraceae) against adults Mexican Bean weevils (Coleoptera: Bruchidae), J Econ Entomol 1994; 87: 1718-25.

(171.) Guenthner E, et al, Pigmentation of egg yolks by xanthophylls from corn, marigold, alfalfa and synthetic sources, Poultry Science 1973; 52: 1787-98.

(172.) Kemin Industries specification sheet, Des Moines, Iowa.

(173.) Carlson Nutrition Handbook, 1992, p. 15, JR Carlson Laboratories, Arlington Heights, Ill.

(174.) Ingold KU, et al, Biokinetics of discrimination between dietary RRR and SRR-a tocopherols in the male rat, Lipids 1987; 22: 163-72.

(175.) National Research Council, Recommended Daily Allowances, National Academy Press 1989, p. 100.

(176.) Acuff RV, et al, Relative bioavailability of RRR- and all-rac alpha tocopheryl acetate in humans: studies using deuterated compounds, Am J Clin Nutrition 1994; 60: 397-402.

(177.) King D, et al, Fat malabsorption in elderly patients with cardiac cachexia, Age and Ageing 1996; 25: 144-49

Townsend Letter for Doctors & Patients.

~~~~~~~~

By Bill Sardi

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