Carotenoids

Epidemiologic evidence of a role for the antioxidant vitamins and carotenoids in cataract prevention.

Am J Clin Nutr, 134(5):352S-355S 1991 Jan

The relationship between antioxidant nutrient status and senile cataract was examined in 77 subjects with cataracts and 35 control subjects with clear lenses. Subjects with low (below the 20th percentile) and moderate (20th-80th percentiles) plasma nutrient and nutrient intake levels of vitamin C, vitamin E, and carotenoids were compared with subjects with high levels (above the 80th percentile). The odds ratio (OR) of cortical (CX) cataract among subjects with low plasma carotenoid levels was 7.2 (P less than 0.05) and the OR of posterior subcapsular (PSC) cataract for persons with low plasma vitamin C was 11.3 (P less than 0.10). Low vitamin C intake was associated with an increased risk of CX (OR = 3.7, P less than 0.10) and PSC (OR = 11.0, P less than 0.05) cataract. Subjects who consumed fewer than 3.5 servings of fruit or vegetables per day had an increased risk of both CX (OR = 5.0, P less than 0.05) and PSC cataract (OR = 12.9, P less than 0.01).

Lutein, lycopene, and their oxidative metabolites in chemoprevention of cancer.

J Cell Biochem Suppl, 134(5):236-46 1995

Numerous epidemiological studies have demonstrated that consuming large quantities of fruits and vegetables reduces the risk for several types of human cancers. Carotenoids are abundant in fruits and vegetables and have been extensively studied as cancer preventive agents. A proposed mechanism of action for the protective effect of carotenoids against cancer is based on their antioxidant capability. Recently, we have isolated and characterized 14 new carotenoids, including seven metabolites from the extracts of human serum/plasma. This brings the total number of identified blood carotenoids to 21. Lutein and lycopene, abundant in most fruits and vegetables as well as human serum, have been shown to possess strong antioxidant capability. Among the metabolites of lutein, four results from oxidation and two from non-enzymatic dehydration. The metabolite of lycopene has been identified as 5,6-dihydroxy-5,6-dihydrolycopene, which apparently results from oxidation of lycopene to an intermediate, lycopene epoxide. This intermediate may undergo metabolic reduction to form the lycopene metabolite. Although in vivo oxidation of lutein to its metabolites has been demonstrated based on data obtained from two human studies, in vivo oxidation of lycopene to its metabolite has not yet been established. Recent preliminary studies involving healthy subjects ingesting purified lutein and zeaxanthin (a dietary dihydroxycarotenoid isomeric to lutein) are presented. We propose a possible antioxidant mechanism of action for lutein and lycopene that leads to formation of the oxidation products of these promising chemopreventive agents.

Vitamins E and C, beta-carotene, and other carotenoids as antioxidants.

Am J Clin Nutr, 64(6 Suppl):1315S-1321S 1995 Dec

Tocopherols and tocotrienols (vitamin E), ascorbic acid (vitamin C), and the carotenoids react with free radicals, notably peroxyl radicals, and with singlet molecular oxygen (1O2), which is the basis for their function as antioxidants. RRR-alpha-Tocopherol is the major peroxyl radical scavenger in biological lipid phases such as membranes or low-density lipoproteins. Ascorbic acid is present in aqueous compartments (eg, cytosol, plasma, and other body fluids) and can reduce the tocopherol radical; it also has several metabolically important cofactor functions in enzyme reactions, especially hydroxylations. These micronutrients need to be regenerated on oxidation in the biological setting, hence the need for further coupling to nonradical reducing systems such as glutathione-glutathione disulfide, dihydrolipoate-lipoate, or NADPH-NADP+ and NADH-NAD+. Carotenoids, such as beta-carotene, lycopene, and some oxycarotenoids, eg, zeaxanthin and lutein, exert antioxidant functions in lipid phases by quenching 1O2 or free radicals. There are pronounced differences in tissue carotenoid patterns, extending also to the distribution between the all-trans and various cis isomers of the respective carotenoids. Physical quenching leaves the structure intact, so that in this mode the carotenoids do not require a regeneration reaction.

Dietary antioxidants and the risk of lung cancer [see comments]

Am J Epidemiol, 134(5):471-9 1991 Sep 1

The relation between the intake of retinoids, carotenoids, vitamin E, vitamin C, and selenium and the subsequent risk of lung cancer was studied among 4,538 initially cancer-free Finnish men aged 20-69 years. During a follow-up of 20 years beginning in 1966-1972, 117 lung cancer cases were diagnosed. Inverse gradients were observed between the intake of carotenoids, vitamin E, and vitamin C and the incidence of lung cancer among nonsmokers, for whom the age-adjusted relative risks of lung cancer in the lowest tertile of intake compared with that in the highest tertile were 2.5 (p value for trend = 0.04), 3.1 (p = 0.12), and 3.1 (p less than 0.01) for the three intakes, respectively. Adjustment for various potential confounding factors did not materially alter the results, and the associations did not seem to be due to preclinical cancer. In the total cohort, there was an inverse association between intake of margarine and fruits and risk of lung cancer. The relative risk of lung cancer for the lowest compared with the highest tertile of margarine intake was 4.0 (p less than 0.001), and that for fruits was 1.8 (p = 0.01). These associations persisted after adjustment for the micronutrient intakes and were stronger among nonsmokers. The results suggest that carotenoids, vitamin E, and vitamin C may be protective against lung cancer among nonsmokers. Food sources rich in these micronutrients may also have other constituents with independent protective effects against lung cancer.

Carotenoid pigments: their possible role in protecting against photooxidation in eyes and photoreceptor cells.

Proc R Soc Lond B Biol Sci, 49(5):71-85 1982 Aug 23

The effect of light on animal tissues is ambivalent. Light is necessary for many functions, e.g. for vision and, as in the flagellate halobacterium, to gain energy. But light is potentially dangerous: it is capable of destroying cells or their components by photooxidation, especially in the presence of sensitizing pigments such as haems and cytochromes, which are ubiquitous in aerobic cells. Several different examples are discussed to show how a compromise is achieved in animal tissues that for functional reasons receive high exposure to light. Carotenoid pigments, present in many eyes and photoreceptors, seem especially suited to protect against the deleterious effects of light because they absorb the dangerous short wavelength part of the light spectrum. In plant tissue, carotenoids are also well known to be capable of 'quenching' photoexcited states of sensitizing pigments and of oxygen, a function that they might have also in animal tissue. A consequence of the considerations is that whenever animal tissues are exposed to higher than usual light levels and/or oxygen pressures cellular damage might occur. Examples are discussed; strategies to circumvent the deleterious effects by photooxidation follow directly from the arguments.

Antioxidant functions of carotenoids.

Free Radic Biol Med, 49(5):617-35 1989

Carotenoid pigments, including hydrocarbons such as beta-carotene or xanthophylls such as lutein and zeaxanthin, are very widely distributed in nature, where they play an important role in protecting cells and organisms against the harmful effects of light, air, and sensitizer pigments. This process has been demonstrated in bacteria, algae, plants, animals, and even in humans in the light-sensitive disease, erythropoietic protoporphyria. The primary mechanism of action of this phenomenon appears to be the ability of carotenoids to quench excited sensitizer molecules as well as quench 1O2. In addition to this protection, and potentially of even greater biological importance, is the fact that carotenoids can also serve as antioxidants under conditions other than photosensitization. This review presents the data available indicating the extent of this important function. Antioxidant action can be documented in both enzymic and nonenzymic systems, and has been reported in subcellular, cellular, and animal studies. In fact, the many reports indicating that carotenoids may possess some anticarcinogenic properties may well be related to their ability to interact with and quench various radical species that can be generated within cells.

Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins.

Am J Clin Nutr, 134(5):1448S-1461S 1995 Dec

Epidemiologic data indicate that individuals with low plasma concentrations of carotenoids and antioxidant vitamins and those who smoke cigarettes are at increased risk for age-related macular degeneration (AMD). Laboratory data show that carotenoids and antioxidant vitamins help to protect the retina from oxidative damage initiated in part by absorption of light. Primate retinas accumulate two carotenoids, lutein and zeaxanthin, as the macular pigment, which is most dense at the center of the fovea and declines rapidly in more peripheral regions. The retina also distributes alpha-tocopherol (vitamin E) in a nonuniform spatial pattern. The region of monkey retinas where carotenoids and vitamin E are both low corresponds with a locus where early signs of AMD often appear in humans. The combination of evidence suggests that carotenoids and antioxidant vitamins may help to retard some of the destructive processes in the retina and the retinal pigment epithelium that lead to age-related degeneration of the macula.

Serologic precursors of cancer: serum micronutrients and the subsequent risk of pancreatic cancer.

Am J Clin Nutr, 49(5):895-900 1989 May

In a nested case-control study the stored, frozen sera from 22 cases of cancer of the pancreas and 44 matched control subjects were assayed for retinol, retinol-binding protein, total carotenoids, beta-carotene, lycopene, vitamin E (alpha-tocopherol), and selenium. Prediagnostic serum levels of lycopene and Se were lower among cases than among matched control subjects. These differences remained after adjustment was made for possible confounding by smoking, educational level, and the other measured serum levels. Low levels of serum vitamin E appeared to have a protective effect but a chance association between vitamin E and cancer of the pancreas could not reasonably be excluded. The association between cancer of the pancreas and serum Se was significant when the data were analyzed as a whole but its effect was seen principally in men.

Intake of carotenoids and retinol in relation to risk of prostate cancer.

J Natl Cancer Inst, 134(5):1767-76 1995 Dec 6

BACKGROUND: Several human studies have observed a direct association between retinol (vitamin A) intake and risk of prostate cancer; other studies have found either an inverse association or no association of intake of beta-carotene (the major provitamin A) with risk of prostate cancer. Data regarding carotenoids other than beta-carotene in relation to prostate cancer risk are sparse. PURPOSE: We concluded a prospective cohort study to examine the relationship between the intake of various carotenoids, retinol, fruits, and vegetables and the risk of prostate cancer. METHODS: Using responses to a validated, semiquantitative food-frequency questionnaire mailed to participants in the Health Professionals Follow-up Study in 1986, we assessed dietary intake for a 1-year period for a cohort of 47,894 eligible subjects initially free of diagnosed cancer. Follow-up questionnaires were sent to the entire cohort in 1988, 1990, and 1992. We calculated the relative risk (RR) for each of the upper categories of intake of a specific food or nutrient by dividing the incidence rate of prostate cancer among men in each of these categories by the rate among men in the lowest intake level. All P values resulted from two-sided tests. RESULTS: Between 1986 and 1992, 812 new cases of prostate cancer, including 773 non-stage A1 cases, were documented. Intakes of the carotenoids beta-carotene, alpha-carotene, lutein, and beta-cryptoxanthin were not associated with risk of non-stage A1 prostate cancer; only lycopene intake was related to lower risk (age- and energy-adjusted RR = 0.79; 95% confidence interval [CI] = 0.64-0.99 for high versus low quintile of intake; P for trend = .04). Of 46 vegetables and fruits or related products, four were significantly associated with lower prostate cancer risk; of the four--tomato sauce (P for trend = .001), tomatoes (P for trend = .03), and pizza (P for trend = .05), but not strawberries--were primary sources of lycopene. Combined intake of tomatoes, tomato sauce, tomato juice, and pizza (which accounted for 82% of lycopene intake) was inversely associated with risk of prostate cancer (multivariate RR = 0.65; 95% CI = 0.44-0.95, for consumption frequency greater than 10 versus less than 1.5 servings per week; P for trend = .01) and advanced (stages C and D) prostate cancers (multivariate RR = 0.47; 95% CI = 0.22-1.00; P for trend = .03). No consistent association was observed for dietary retinol and risk of prostate cancer. CONCLUSIONS: These findings suggest that intake of lycopene or other compounds in tomatoes may reduce prostate cancer risk, but other measured carotenoids are unrelated to risk. IMPLICATIONS: Our findings support recommendations to increase vegetable and fruit consumption to reduce cancer incidence but suggest that tomato-based foods may be especially beneficial regarding prostate cancer risk.

Serum antioxidants and age-related macular degeneration in a population-based case-control study.

Arch Ophthalmol, 134(5):1518-23 1995 Dec

OBJECTIVE: To investigate relationships between levels of tocopherols and carotenoids in the serum and age-related macular degeneration (ARMD). DESIGN: A nested case-control study within a population-based cohort. PARTICIPANTS: Cases included a sample of subjects with retinal pigment abnormalities with the presence of soft drusen (n = 127) or with late ARMD (geographic atrophy [n = 9]) or neovascular and exudative macular degeneration (n = 31). An equal number of controls (167 pairs) were selected from among participants in the Beaver Dam Eye Study. The controls had no photographic evidence of soft drusen, retinal pigment abnormalities, or late ARMD and were matched with cases for age, sex, and current smoking status. DATA COLLECTION: Presence and severity of ARMD were determined from masked grading of fundus photographs obtained from 1988 to 1990. Levels of individual carotenoids and tocopherols were determined in serum collected at the same time. RESULTS: Average levels of individual carotenoids were similar in cases and controls. Average levels of vitamin E (alpha-tocopherol) were lower in people with exudative macular degeneration (P = .03). However, the difference was no longer statistically significant after controlling for levels of cholesterol in the serum. Persons with levels of lycopene, the most abundant carotenoid in the serum, in the lowest quintile were twice as likely to have ARMD. Levels of the carotenoids that compose macular pigment (lutein with zeaxanthin) in the serum were unrelated to ARMD. CONCLUSIONS: Very low levels of one (lycopene) but not other dietary carotenoids or tocopherols were related to ARMD. Lower levels of vitamin E in subjects with exudative macular degeneration compared with controls may be explained by lower levels of serum lipids.

Serum carotenoids and coronary heart disease. The Lipid Research Clinics Coronary Primary Prevention Trial and Follow-up Study [see comments]

JAMA 272(18): 1439-41 (1994)

OBJECTIVE--To examine the relationship between total serum carotenoid levels and the risk of subsequent coronary heart disease (CHD) events. DESIGN--New analysis of a cohort from the Lipid Research Clinics Coronary Primary Prevention Trial and Follow-up Study (LRC-CPPT). The LRC-CPPT was a multicenter placebo-controlled trial of cholestyramine resin and CHD with a follow-up period of 13 years. Serum carotenoids were measured at baseline. PARTICIPANTS--The placebo group of the LRC- CPPT, which consisted of 1899 men aged 40 to 59 years with type II-a hyperlipidemia and without known preexisting CHD, cancer, or other major illnesses. MAIN OUTCOME MEASURES--Nonfatal myocardial infarctions and deaths attributable to CHD ascertained from hospital records, autopsy reports, and death certificates and reviewed by a panel of cardiologists. RESULTS--After adjustment for known CHD risk factors including smoking, serum carotenoids were inversely related to CHD events. Men in the highest quartile of serum carotenoids had an adjusted relative risk (RR) of 0.64 (95% confidence interval [CI], 0.44 to 0.92) compared with the lowest quartile. For men who never smoked, this RR was 0.28 (95% CI, 0.11 to 0.73). CONCLUSIONS--The LRC-CPPT participants with higher serum carotenoid levels had a decreased risk of incident CHD. This finding was stronger among men who never smoked.

Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group [see comments] [published erratum appears in JAMA 1995 Feb 22;273(8):622]

JAMA, 1994 Nov, 272:18, 1413-20

OBJECTIVE--To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults. DESIGN--The multicenter Eye Disease Case-Control Study. SETTING--Five ophthalmology centers in the United States. PATIENTS--A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex. MAIN OUTCOME MEASURES--The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses. RESULTS--A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92; P for trend = .02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (P for trend = .001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (P for trend < .001). The intake of preformed vitamin A (retinol) was not appreciably related to AMD. Neither vitamin E nor total vitamin C consumption was associated with a statistically significant reduced risk for AMD, although a possibly lower risk for AMD was suggested among those with higher intake of vitamin C, particularly from foods. CONCLUSION--Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. These findings support the need for further studies of this relationship.

Supplementation with carotenoids corrects increased lipid peroxidation in children with cystic fibrosis [published erratum appears in Am J Clin Nutr 1997 Feb;65(2):578] [see comments]

Am J Clin Nutr, 64(1):87-93 1996 Jul

Evidence of lipid peroxidation previously documented in cystic fibrosis (CF) implies an imbalance between free radical generation and antioxidant defense mechanisms. The aim of the present study was to examine the relation between plasma concentrations of malondialdehyde, a marker of lipid peroxidation, and the exogenous antioxidant line of defense. Malondialdehyde concentrations (90.2 +/- 4.7 nmol/L) in 25 children with CF aged 9.6 +/- 0.8 y were higher (P < 0.001) than concentrations (69.1 +/- 2.6 nmol/L) in 17 children used as control subjects and were not correlated with any marker of disease severity. In contrast with their all-rac-alpha-tocopherol status, which was normal as a result of routine supplementation with a 200-mg dose of all-rac-alpha-tocopheryl acetate/d, beta-carotene was very low. A 2-mo open trial in which 12 children with CF aged 11.5 +/- 0.8 y were given 4.42 mg (8.23 mumol) beta-carotene three times per day led to normalization of the malondialdehyde concentration in all but 1 patient, in conjunction with an increase of plasma beta-carotene from 0.08 +/- 0.03 to 3.99 +/- 0.92 mumol/L. Their plasma concentrations were inversely correlated (r = -0.54, P = 0.006) [corrected] with malondialdehyde when the values measured pre- and posttreatment were pooled. We conclude that beta-carotene deficiency contributes to lipid peroxidation in CF and that supplementation may eventually prove to be a useful adjunct for the management of the disease.

Antioxidants and reduced functional capacity in the elderly: findings from the Nun Study.

J Gerontol A Biol Sci Med Sci, 64(1):M10-6 1996 Jan

BACKGROUND. This study investigated the relationship of plasma antioxidants to reduced functional capacity in the elderly. A hallmark of reduced functional capacity in the elderly is dependence in self-care (i.e., requiring assistance with bathing, walking, dressing, standing, toileting, and feeding). METHODS. This relationship was assessed in a cross-sectional study of 88 Catholic sisters (nuns). These 77- to 98-year-old women lived in the same building, ate food prepared in the same kitchen, and had all nursing services provided by the same staff. In 1993, ability to perform self-care was assessed, and blood was drawn to determine plasma carotenoids (lycopene, beta carotene, alpha carotene, zeaxanthin and lutein combined, and beta cryptoxanthin) and alpha tocopherol. RESULTS. Dependence in self-care had a strong negative association with lycopene, but was not clearly related to other carotenoids or alpha tocopherol. Results from age-adjusted least squares regression indicated that a 30 micrograms/dl decrease in lycopene was associated with 2.4 additional dependencies in self-care (95% confidence interval = 1.5, 3.3; p <.001). Lycopene's relationship to dependence was modified by plasma LDL-cholesterol, the predominant carrier of lycopene in the blood. Women with low lycopene and low LDL-cholesterol had 3.6 dependencies (95% confidence interval = 3.1, 4.2; p ><.001), compared to 1.0 dependency (95% confidence interval = 0.3, 1.8) in those with high lycopene and low LDL-cholesterol. CONCLUSIONS. This is the first study to report an association between lycopene and functional status. This finding needs to be replicated in other human and animal studies before the association is accepted as real.>< .001). Lycopene's relationship to dependence was modified by plasma LDL-cholesterol, the predominant carrier of lycopene in the blood. Women with low lycopene and low LDL-cholesterol had 3.6 dependencies (95% confidence interval = 3.1, 4.2; p < .001), compared to 1.0 dependency (95% confidence interval = 0.3, 1.8) in those with high lycopene and low LDL-cholesterol. CONCLUSIONS. This is the first study to report an association between lycopene and functional status. This finding needs to be replicated in other human and animal studies before the association is accepted as real.

Plasma concentrations of vitamins A and E and carotenoids in Alzheimer's disease.

Age Ageing, 21(2):91-4 1992 Mar

In a case/control study, serum concentrations of vitamins A and E and major carotenoids were determined in patients with Alzheimer's disease, multi-infarct dementia and control subjects. The results showed that both Alzheimer's and multi-infarct dementia patients had significantly lower levels of vitamin E and beta-carotene than controls (vitamin E: 18.65 +/- 3.62 mumol/l in Alzheimer's disease and 15.80 +/- 6.93 mumol/l in multi-infarct dementia versus 30.03 +/- 12.03 mumol/l in controls; beta-carotene less than 0.13 to 0.42 mumol/l in Alzheimer's disease and less than 0.13 to 0.30 mumol/l in multi-infarct dementia versus 0.13 to 1.53 mumol/l in controls). Vitamin A was significantly reduced only in the Alzheimer's patients (1.56 +/- 0.78 mumol/l in Alzheimer's disease versus 2.13 +/- 0.86 mumol/l in controls).

Antioxidant functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids.

Ann N Y Acad Sci, 669(-VI-):7-20 1992 Sep 30

Tocopherols and tocotrienols (vitamin E) and ascorbic acid (vitamin C) as well as the carotenoids react with free radicals, notably peroxyl radicals, and with singlet molecular oxygen (1O2), this being the basis of their function as antioxidants. RRR-alpha-tocopherol is the major peroxyl radical scavenger in biological lipid phases such as membranes or low-density lipoproteins (LDL). L-Ascorbate is present in aqueous compartments (e.g. cytosol, plasma, and other body fluids) and can reduce the tocopheroxyl radical; it also has a number of metabolically important cofactor functions in enzyme reactions, notably hydroxylations. Upon oxidation, these micronutrients need to be regenerated in the biological setting, hence the need for further coupling to nonradical reducing systems such as glutathione/glutathione disulfide, dihydrolipoate/lipoate, or NADPH/NADP+ and NADH/NAD+. Carotenoids, notably beta-carotene and lycopene as well as oxycarotenoids (e.g. zeaxanthin and lutein), exert antioxidant functions in lipid phases by free-radical or 1O2 quenching. There are pronounced differences in tissue carotenoid patterns, extending also to the distribution between the all-trans and various cis isomers of the respective carotenoids. Antioxidant functions are associated with lowering DNA damage, malignant transformation, and other parameters of cell damage in vitro as well as epidemiologically with lowered incidence of certain types of cancer and degenerative diseases, such as ischemic heart disease and cataract. They are of importance in the process of aging. Reactive oxygen species occur in tissues and cells and can damage DNA, proteins, carbohydrates, and lipids. These potentially deleterious reactions are controlled in part by antioxidants that eliminate prooxidants and scavenge free radicals. Their ability as antioxidants to quench radicals and 1O2 may explain some anticancer properties of the carotenoids independent of their provitamin A activity, but other functions may play a role as well. Tocopherols are the most abundant and efficient scavengers of peroxyl radicals in biological membranes. The water-soluble antioxidant vitamin C can reduce tocopheroxyl radicals directly or indirectly and thus support the antioxidant activity of vitamin E; such functions can be performed also by other appropriate reducing compounds such as glutathione (GSH) or dihydrolipoate. The biological efficacy of the antioxidants is also determined by their biokinetics.

Emerging role of beta-carotene and antioxidant nutrients in prevention of oral cancer.

Arch Otolaryngol Head Neck Surg, 121(2):141-4 1995 Feb

beta-carotene and other antioxidant nutrients, such as vitamin E, are well suited for widespread preventive use because they are nontoxic and easily given in supplement form. Intervention trials designed to show a reduction of cancer incidence in the general population are logistically and practically impossible for most types of cancer, including cancer of the oral cavity. Thus evidence for chemoprevention must be indirect, using laboratory and animal models, epidemiologic surveys, and trials showing reversal of premalignant lesions or cancer prevention in high-risk groups. In several animal models, beta-carotene and other antioxidant nutrients inhibit oral carcinogenesis. Epidemiologic studies consistently relate low intake of these nutrients with high cancer risk. Smokers have lower beta-carotene levels in plasma and oral mucosal cells than nonsmokers. Eight clinical trials have now shown that beta-carotene and vitamin E produce regression of oral leukoplakia, but chemoprevention studies in oral leukoplakia have limitations, which we review. All available evidence supports a significant role for antioxidant nutrients in preventing oral cancer.

Vitamin E, selenium, trolox C, ascorbic acid palmitate, acetylcysteine, coenzyme Q, beta-carotene, canthaxanthin, and (+)-catechin protect against oxidative damage to kidney, heart, lung and spleen.

Free Radic Res, 22(2):177-86 1995 Feb

Male Sprague-Dawley rats were fed diets that varied qualitatively and quantitatively in antioxidants. Kidney, heart, lung, and spleen homogenates were incubated at 37 degrees C with and without hydroperoxide or Fe+2. Protection of antioxidants against oxidative damage to tissue was determined by measurement of oxidized heme proteins. Tissues from rats supplemented with dietary vitamin E and selenium showed protection compared to tissues from rats on the basal diet. Tissues from rats with diets containing larger quantities of antioxidants and both fat soluble antioxidants: vitamin E, beta-carotene, coenzyme Q10, ascorbic acid 6-palmitate and water soluble antioxidants: selenium, trolox C, acetylcysteine, coenzyme Q0, (+)-catechin, showed the highest protection.

Epidemiologic evidence of a role for the antioxidant vitamins and carotenoids in cataract prevention.

Am J Clin Nutr, 53(1 Suppl):352S-355S 1991 Jan

The relationship between antioxidant nutrient status and senile cataract was examined in 77 subjects with cataracts and 35 control subjects with clear lenses. Subjects with low (below the 20th percentile) and moderate (20th-80th percentiles) plasma nutrient and nutrient intake levels of vitamin C, vitamin E, and carotenoids were compared with subjects with high levels (above the 80th percentile). The odds ratio (OR) of cortical (CX) cataract among subjects with low plasma carotenoid levels was 7.2 (P less than 0.05) and the OR of posterior subcapsular (PSC) cataract for persons with low plasma vitamin C was 11.3 (P less than 0.10). Low vitamin C intake was associated with an increased risk of CX (OR = 3.7, P less than 0.10) and PSC (OR = 11.0, P less than 0.05) cataract. Subjects who consumed fewer than 3.5 servings of fruit or vegetables per day had an increased risk of both CX (OR = 5.0, P less than 0.05) and PSC cataract (OR = 12.9, P less than 0.01).

Antioxidant defense systems: the role of carotenoids, tocopherols, and thiols.

Am J Clin Nutr, 53(1 Suppl):194S-200S 1991 Jan

Reactive oxygen species occur in tissues and can damage DNA, proteins, carbohydrates, and lipids. These potentially deleterious reactions are controlled by a system of enzymatic and nonenzymatic antioxidants which eliminate prooxidants and scavenge free radicals. The ability of the lipid-soluble carotenoids to quench singlet molecular oxygen may explain some anticancer properties of the carotenoids, independent of their provitamin A activity. Tocopherols are the most abundant and efficient scavengers of hydroperoxyl radicals in biological membranes. Water-soluble antioxidants include ascorbate and cellular thiols. Glutathione is an important substrate for enzymatic antioxidant functions and is capable of nonenzymatic radical scavenging. Thiols associated with membrane proteins may also be important to the antioxidant systems. Interactions between the thiols, tocopherols, and other compounds enhance the effectiveness of cellular antioxidant defense.

The effect of beta-carotene supplementation on the immune function of blood monocytes from healthy male nonsmokers [see comments]

J Lab Clin Med, 1997 Mar, 129:3, 309-17

Although there is strong epidemiologic evidence that diets rich in carotenoids such as beta-carotene are associated with a reduced incidence of cancer, the cellular mechanisms underlying this phenomenon remain unknown. This article describes the effect of dietary beta-carotene supplementation on both the expression of functionally associated surface molecules on human monocytes and on the secretion of the cytokine tumor necrosis factor-alpha (TNF-alpha) by monocytes, all of which are involved in the initiation and regulation of immune responses involved in tumor surveillance. A double-blind, placebo-controlled, crossover study was undertaken in which 25 healthy, adult male nonsmokers were randomly assigned to receive beta-carotene (15 mg daily) or placebo for 26 days, followed by the alternative treatment for a further 26 days. The expression of functionally related monocyte surface molecules was quantified by flow cytometry, and ex vivo secretion of TNF-alpha was quantified by an enzyme-linked immunosorbent assay, before and after each treatment period. After dietary supplementation there were significant increases in plasma levels of beta-carotene and in the percentages of monocytes expressing the major histocompatibility complex class II molecule HLA-DR and the adhesion molecules intercellular adhesion molecule-1 and leukocyte function-associated antigen-3. In addition, the ex vivo TNF-alpha secretion by blood monocytes was significantly increased after supplementation. These findings suggest that moderate increases in the dietary intake of beta-carotene can enhance cell-mediated immune responses within a relatively short period of time, providing a potential mechanism for the anticarcinogenic properties attributed to beta-carotene.

The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group [see comments]

N Engl J Med, 1994 Apr, 330:15, 1029-35

BACKGROUND. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. METHODS. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. RESULTS. Among the 876 new cases of lung cancer diagnosed during the trial, no reduction in incidence was observed among the men who received alpha-tocopherol (change in incidence as compared with those who did not, -2 percent; 95 percent confidence interval, -14 to 12 percent). Unexpectedly, we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18 percent; 95 percent confidence interval, 3 to 36 percent). We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer. Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not. Beta carotene had little or no effect on the incidence of cancer other than lung cancer. Alpha-tocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Total mortality was 8 percent higher (95 percent confidence interval, 1 to 16 percent) among the participants who received beta carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease. CONCLUSIONS. We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.

Protection of vitamin E, selenium, trolox C, ascorbic acid palmitate, acetylcysteine, coenzyme Q0, coenzyme Q10, beta-carotene, canthaxanthin, and (+)-catechin against oxidative damage to rat blood and tissues in vivo.

Free Radic Biol Med, 18(5):949-53 1995 May

Male Sprague-Dawley rats were fed either a vitamin E and selenium deficient diet, a diet supplemented with vitamin E and selenium, or a diet supplemented with vitamin E, selenium, trolox C, ascorbic acid palmitate, acetylcysteine, Beta-carotene, canthaxanthin, coenzyme Q0, coenzyme Q10, and (+)-catechin. Rats were injected with CBrCl3 (0.05 mmol/100 g body weight) intraperitoneally. Oxidative damage to tissues was measured by formation of oxidized heme proteins (OHP) in blood, liver, kidney, heart, lung, and spleen. Diets supplemented with antioxidants showed protection against oxidative damage caused by CBrCl3. The protection was dependent on the diversity and quantity of antioxidants in the diet. In general, diets supplemented with both fat soluble and water soluble antioxidants provided better protection than diets supplemented only with vitamin E and selenium or with vitamin E, selenium, and fat soluble antioxidants.

Lack of improvement in vitamin A status with increased consumption of dark-green leafy vegetables [see comments]

Lancet, 346(8967):75-81 1995 Jul 8

There is little evidence to support the general assumption that dietary carotenoids can improve vitamin A status. We investigated in Bogor District, West Java, Indonesia, the effect of an additional daily portion of dark-green leafy vegetables on vitamin A and iron status in women with low haemoglobin concentrations (<130 g/L) who were breastfeeding a child of 3-17 months. Every day for 12 weeks one group (n = 57) received stir-fried vegetables, a second (n = 62) received a wafer enriched with beta-carotene, iron, vitamin C, and folic acid, and a third (n = 56) received a non-enriched wafer to control for additional energy intake. The vegetable supplement and the enriched wafer contained 3.5 mg beta-carotene, 5.2 mg and 4.8 mg iron, and 7.8 g and 4.4 g fat, respectively. Assignment to vegetable or wafer groups was by village. Wafers were distributed double-masked. In the enriched-wafer group there were increases in serum retinol (mean increase 0.32 [95% CI 0.23-0.40] mumol/L), breastmilk retinol (0.59 [0.35-0.84] mumol/L), and serum beta-carotene (0.73 [0.59-0.88] mumol/L). These changes differed significantly from those in the other two groups, in which the only significant changes were small increases in breastmilk retinol in the control-wafer group (0.16 [0.02-0.30] mumol/L) and in serum beta-carotene in the vegetable group (0.03 [0-0.06] mumol/L). Changes in iron status were similar in all three groups. An additional daily portion of dark-green leafy vegetables did not improve vitamin A status, whereas a similar amount of beta-carotene from a simpler matrix produced a strong improvement. These results suggest that the approach to combating vitamin A deficiency by increases in the consumption of provitamin A carotenoids from vegetables should be re-examined.>< 130 g/L) who were breastfeeding a child of 3-17 months. Every day for 12 weeks one group (n = 57) received stir-fried vegetables, a second (n = 62) received a wafer enriched with beta-carotene, iron, vitamin C, and folic acid, and a third (n = 56) received a non-enriched wafer to control for additional energy intake. The vegetable supplement and the enriched wafer contained 3.5 mg beta-carotene, 5.2 mg and 4.8 mg iron, and 7.8 g and 4.4 g fat, respectively. Assignment to vegetable or wafer groups was by village. Wafers were distributed double-masked. In the enriched-wafer group there were increases in serum retinol (mean increase 0.32 [95% CI 0.23-0.40] mumol/L), breastmilk retinol (0.59 [0.35-0.84] mumol/L), and serum beta-carotene (0.73 [0.59-0.88] mumol/L). These changes differed significantly from those in the other two groups, in which the only significant changes were small increases in breastmilk retinol in the control-wafer group (0.16 [0.02-0.30] mumol/L) and in serum beta-carotene in the vegetable group (0.03 [0-0.06] mumol/L). Changes in iron status were similar in all three groups. An additional daily portion of dark-green leafy vegetables did not improve vitamin A status, whereas a similar amount of beta-carotene from a simpler matrix produced a strong improvement. These results suggest that the approach to combating vitamin A deficiency by increases in the consumption of provitamin A carotenoids from vegetables should be re-examined.

Nutrition supplements and the eye.

Eye, 24(7-8):127-33 1998

PURPOSE: A review of the role of vitamins, minerals, carotenoids and essential fatty acids in relation to eye health. The mode of action may be directly on the eye or by promoting bodily health on which the eye depends. RESULTS: The lens and retina suffer oxidative damage and the anti-oxidant vitamins A, C and E are implicated as protective. Studies in man give indifferent support to the role of nutrition in the development of cataract. In the elderly, vitamin intake may be inadequate, so that a vitamin supplement may be reasonable. Zinc has a role in retinal metabolism and may be beneficial in macular degeneration. Selenium has an anti-oxidant role. Other minerals including copper have a less defined role. Carotenoids are concentrated at the macula and have an anti-oxidant role. A reduced risk of macular degeneration is found in relation to a high serum level. The essential fatty acid, gamma-linolenic acid (GLA), is useful in Sj¨ogren's syndrome and may help in other dry eye conditions. Omega-3 fatty acids are important in retinal development and have a role in preventing cardiovascular disease. CONCLUSION: All persons should be encouraged to maintain healthy nutrition. Middle-aged and elderly patients may benefit from a supplement. An intake in excess of the recommended daily intake may be beneficial, but this is not proven. Further clinical trials are indicated to define the advisability of vitamin, mineral and other supplements. Dosages for recommended intake and for supplements are given.

The significance of vitamin A and carotenoid status in persons infected by the human immunodeficiency virus.

Clin Infect Dis, 26(3):711-8 1998 Mar

Hyporetinemia is associated with increased childhood morbidity and mortality that is reversible with vitamin A supplementation. Although vitamin A deficiency is otherwise rare in developed countries, the prevalence of hyporetinemia in human immunodeficiency virus (HIV)-infected persons is up to 29%. Hyporetinemic HIV-infected patients have a 3.5-5-fold increased risk of death. Furthermore, HIV-infected patients with very low or very high intake of vitamin A and beta-carotene (a vitamin A precursor) have greater rates of disease progression than do patients with intermediate intake. In developing countries up to 60% of HIV-infected pregnant women are hyporetinemic. In such women the relative risk of perinatal HIV transmission may be increased more than fourfold. These data indicate that vitamin A deficiency is common in HIV-infected patients in the developed world and strongly suggest that vitamin A supplementation may be especially useful in adjunctive therapy for HIV-infected pregnant women who reside in the developing world.

Antioxidant status in persons with and without senile cataract.

Arch Ophthalmol, 106(3):337-40 1988 Mar

The relationship between biochemical markers of antioxidant status and senile cataract was examined in 112 subjects aged 40 to 70 years. Seventy-seven of these subjects had a cataract in at least one lens. Antioxidant status was measured using erythrocyte superoxide dismutase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase activity, and indexes that included these enzymes plus plasma levels of vitamin E, vitamin C, and carotenoids. Subjects were grouped by level (low, moderate, or high) of the enzymes and antioxidant indexes. Results suggest that subjects with high levels of at least two of the three vitamins (vitamin E, vitamin C, or carotenoids) are at reduced risk of cataract relative to subjects with low levels of one or more of these vitamins (odds ratio, 0.2). The erythrocyte enzymes, either individually or in combination, did not appear to differ between subjects with and without cataract.

Systemic oxidative stress and cognitive performance in the population-based EVA study. Etude du Vieillissement Art´eriel.

Free Radic Biol Med, 24(7-8):1202-8 1998 May

The aim of this study was to examine the relationships between cognitive functioning and blood levels of antioxidants and lipoperoxidation products in an elderly population. In 1991-1992, 1389 volunteers (574 men and 815 women aged 59 to 71 years) were recruited from the general population. Levels of selenium, carotenoids, and thiobarbituric-reactive substances in plasma and of vitamin E, glutathione peroxidase, and Cu-Zn superoxide dismutase in red blood cells were measured. Cognitive functioning was assessed with various psychometric tests. We used logistic regression to estimate the risk of poor cognitive functioning (<25th percentile of the score distribution) associated with low values of each antioxidants (><25th percentile) including potential confounding factors. A low level of total carotenoids (><1.86 mumol/l) was associated with poor cognitive performance in two tests assessing visual attention and logical reasoning: the Trail-Making Test part B [OR = 1.34 IC95% (0.99-1.81), p = .055] and the Digit Symbol Substitution from the WAIS-R [OR = 1.38 IC95% (1.02-1.89), p = .04]. Low levels of other antioxidants and high levels of thiobarbituric-reactive substances were not related to poor cognitive functioning. Results observed with plasma carotenoids are in accordance with previous data obtained mostly from dietary records.>< 25th percentile of the score distribution) associated with low values of each antioxidants (< 25th percentile) including potential confounding factors. A low level of total carotenoids (< 1.86 mumol/l) was associated with poor cognitive performance in two tests assessing visual attention and logical reasoning: the Trail-Making Test part B [OR = 1.34 IC95% (0.99-1.81), p = .055] and the Digit Symbol Substitution from the WAIS-R [OR = 1.38 IC95% (1.02-1.89), p = .04]. Low levels of other antioxidants and high levels of thiobarbituric-reactive substances were not related to poor cognitive functioning. Results observed with plasma carotenoids are in accordance with previous data obtained mostly from dietary records.

Inhibitory effects of alpha-carotene on proliferation of the human neuroblastoma cell line GOTO.

J Natl Cancer Inst, 81(21):1649-52 1989 Nov 1

alpha-Carotene inhibited the proliferation of the human neuroblastoma cell line GOTO in a dose- and time-dependent manner. In addition, it was about 10 times more inhibitory than beta-carotene. Northern blot analysis indicated that alpha-carotene caused maximum suppression of the level of the N-myc messenger RNA of GOTO cells. This suppression occurred within 18 hours of alpha-carotene treatment, after which the level of the N-myc messenger RNA gradually recovered to the basal level. Analysis by flow cytometry indicated that when GOTO cells were exposed to alpha-carotene, they were arrested in the G0-G1 phase of their cell cycle. However, as the level of the N-myc messenger RNA was recovering, these cells resumed normal cycling. These results indicate that the reduction in the level of the N-myc messenger RNA caused by alpha-carotene is closely linked with G0-G1 arrest.

Potent preventive action of alpha-carotene against carcinogenesis: spontaneous liver carcinogenesis and promoting stage of lung and skin carcinogenesis in mice are suppressed more effectively by alpha-carotene than by beta-carotene.

Cancer Res, 52(23):6583-7 1992 Dec 1

Although beta-carotene has been considered to be a key cancer preventive agent in green and yellow vegetables, other types of carotenoids, such as alpha-carotene, may also contribute to anticarcinogenic action, since these carotenoids usually coexist with beta-carotene and are detectable in human blood and tissues. In this study, we compared the inhibitory effect of natural alpha-carotene, obtained from palm oil, with that of beta-carotene on spontaneous liver carcinogenesis in C3H/He male mice. The mean number of hepatomas per mouse was significantly decreased by alpha-carotene supplementation (per os administration in drinking water at a concentration of 0.05%, ad libitum) as compared with that in the control group (P <0.001, Student's t test). On the other hand, beta-carotene, at the same dose as alpha-carotene, did not show any such significant difference from the control group. Furthermore, we also compared the antitumor-promoting activity of alpha-carotene with that of beta-carotene against two-stage mouse lung carcinogenesis (initiator, 4-nitroquinoline 1-oxide; promoter, glycerol). alpha-Carotene, but not beta-carotene, reduced the number of lung tumors per mouse to about 30% of that in the control group (P ><0.001, Student's t test). The higher potency of the antitumor-promoting action of alpha-carotene compared to beta-carotene was confirmed in other experimental systems; e.g., alpha-carotene was also found to have a stronger effect than beta-carotene in suppressing the promoting activity of 12-O-tetradecanoylphorbol-13-acetate on skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated mice. These results suggest that not only beta-carotene, but also other types of carotenoids, such as alpha-carotene, may play an important role in cancer prevention.>< 0.001, Student's t test). On the other hand, beta-carotene, at the same dose as alpha-carotene, did not show any such significant difference from the control group. Furthermore, we also compared the antitumor-promoting activity of alpha-carotene with that of beta-carotene against two-stage mouse lung carcinogenesis (initiator, 4-nitroquinoline 1-oxide; promoter, glycerol). alpha-Carotene, but not beta-carotene, reduced the number of lung tumors per mouse to about 30% of that in the control group (P < 0.001, Student's t test). The higher potency of the antitumor-promoting action of alpha-carotene compared to beta-carotene was confirmed in other experimental systems; e.g., alpha-carotene was also found to have a stronger effect than beta-carotene in suppressing the promoting activity of 12-O-tetradecanoylphorbol-13-acetate on skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated mice. These results suggest that not only beta-carotene, but also other types of carotenoids, such as alpha-carotene, may play an important role in cancer prevention.

Effect of a single oral dose of antioxidant mixture (vitamin E, carotenoids) on the formation of cholesterol oxidation products after ex vivo LDL oxidation in humans.

Eur J Med Res, 3(1-2):5-12 1998 Feb 21

During oxidation of LDL not only polyunsaturated fatty acids and apolipoproteins but also cholesterol is affected. To test the preventive effect of vitamin E and carotenoids against metal ion-induced oxidative modification of the cholesterol moiety, LDL of five females (age 25-30 years) were enriched by single oral supplementation with a mixture of alpha-tocopherol, beta-carotene, lycopene, canthaxanthin, and lutein. LDL was isolated from blood samples before as well as 10 and 24 hours after supplement intake. In the 10 and 24 hours samples, total concentration of the supplemented antioxidants increased significantly to 127% and 125% of the initial value, respectively. As a consequence, the lag phase until beginning of oxidative modification of fatty acids--measured in terms of lag phase time till diene production--significantly increased by 13% (10 h and 24 h). After stopping the oxidation process in all LDL samples (0 h, 10 h, 24 h) of one person when the maximal absorbance value of diene production in the 10 h sample was reached, a statistically significant reduction in the formation of cholesterol oxidation products (COP) could be measured. In the average, 10 h and 24 h after supplementation the COP concentration reached 84% and 86% of the 0 h-value, respectively. Except for 7 beta-hydroxycholesterol, all COP measured decreased by 10-20%. The results of the in vitro-model demonstrate that an antioxidant enrichment of LDL has the potential to protect also cholesterol (besides unsaturated fatty acids) against oxidative modification.

Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States)

Cancer Causes Control, 9(1):89-97 1998 Jan

To evaluate relationships of serum carotenoids, alpha-tocopherol, selenium, and retinol with breast cancer prospectively, we conducted a case-control study nested in a cohort from the Breast Cancer Serum Bank in Columbia, Missouri (United States). Women free of cancer donated blood to this bank in 1977-87. During up to 9.5 years of follow-up (median = 2.7 years), 105 cases of histologically confirmed breast cancer were diagnosed. For each case, two women alive and free of cancer at the age of the case's diagnosis and matched on age and date of blood collection were selected as controls. A nonsignificant gradient of decreasing risk of breast cancer with increasing serum beta-cryptoxanthin was apparent for all women. Serum lycopene also was associated inversely with risk, and among women who donated blood at least two years before diagnosis, a significant gradient of decreasing breast cancer risk with increasing lycopene concentration was evident. A marginally significant gradient of decreasing risk with increasing serum lutein/zeaxanthin also was apparent among these women. We did not observe any evidence for protective effects of alpha- and beta-carotene, alpha-tocopherol, retinol, or selenium for breast cancer. Results of this study suggest that the carotenoids beta-cryptoxanthin, lycopene, and lutein/zeaxanthin may protect against breast cancer.