Dietary carotenoids are associated with decreased risk of cardiovascular disease and cancer; however, -carotene supplementation does not decrease the risk of any disease.

[DFM ] Letter Key

Description

• Carotenoids are orange, yellow, and red pigments present in many vegetables and fruits.
• There are more than 600 carotenoids, all of which are polyisoprenoids that possess numerous conjugated double bonds.
• About 50 carotenoids serve as vitamin A precursors, including the most common carotenoids in human serum: lutein, lycopene, zeaxanthin, -cryptoxanthin, -carotene, and -carotene.

Food Sources

• Carotenoids are found in many vegetables and fruits, as well as in red palm oil. -Carotene is found in orange, red, and dark green vegetables and fruits (carrots and pumpkins are especially high in -carotene).
• Lycopene is found in tomato products, watermelon, guava, and in smaller amounts in pink grapefruit.

Main Functions/Pharmacokinetics

• Carotenoids enhance cell-to-cell communication, enhance differentiation of cells, modulate the immune response, and may affect reproductive performance (1).
• Besides being important precursors of vitamin A, carotenoids quench singlet oxygen and have both antioxidant and prooxidant properties, depending on the environment. Carotenoids can form radical cations or anions (highly reactive molecules that can react with other free radicals to create nonradical products) or can interact with other molecules, restoring the carotenoid to the ground state while producing a new free radical. Antioxidant properties usually predominate in physiologic conditions.

[Outline]

• DDescription
• FFood Sources
• MMain Functions/Pharmacokinetics

[C ] Letter Key

Epidemiologic studies have linked intake of foods high in -carotene with decreased risk of cancer of the lung, head and neck, gastrointestinal tract, breast, and prostate, as well as ischemic heart disease, stroke, and age-related macular degeneration (2). However, -carotene supplementation trials in those at high risk of lung cancer or cardiovascular disease have found either no benefit or increased risk.

Clinical Trials

• Cancer prevention
  • Two of three randomized controlled trials of the effect of -carotene on lung cancer risk found an adverse effect of supplementation; the third found no effect. In the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study, 29,133 Finnish smokers 50 to 69 years old were treated with -carotene 20 mg for 5 to 8 years. There was a higher rate of lung cancer [relative risk (RR) 1.18] and total mortality (RR 1.08) in the group treated with -carotene than in those treated with placebo (3).
  • The Carotene and Retinol Efficacy Trial (CARET) tested -carotene (30 mg/day) and retinyl ester (25,000 IU) against placebo in smokers and asbestos workers; the trial was prematurely terminated after 4 years because of increased lung cancer (RR = 1.28) and increased total mortality (RR = 1.17) in the supplemented group (4).
  • In the Physicians Health Study, there were no differences between those supplemented with -carotene capsules (50 mg every other day) and the unsupplemented group in lung cancer incidence, cancer deaths, or deaths from any cause (5).
• Pancreatic cancer
  • In the ATBC trial, -carotene had no effect on the incidence of pancreatic cancer or rate of mortality (6).
• Skin cancer
  • In a study of 1,805 participants previously diagnosed with nonmelanoma skin cancer, there was no difference in recurrence of basal-cell or squamous-cell skin cancers by -carotene supplementation (50 mg/day over 5 years) compared with placebo (7).
• Precancerous conditions
  • Although dietary intake of carotenoids is linked with a lower rate of cervical cancer, two randomized, placebo-controlled trials of -carotene supplementation (10 mg/day × 3 months in 333 women or 30 mg/day × 9 months in 98 women) found no difference between treatment and placebo in regression of cervical dysplasia (8). A recent, longer randomized placebo-controlled trial of 141 women with minor squamous atypia or cervical intraepithelial neoplasia (CIN)-1 tested 30 mg -carotene, 500 mg vitamin C, or both for 2 years and found no effect of either supplement (9).
  • In clinical trials, -carotene supplements reduced oral leukoplakia but had no effect on colorectal adenomas or sputum atypia (1).
• Cardiovascular disease prevention
  • The incidence of cardiovascular disease deaths in the ATBC study was increased 11% in the -carotene-supplemented group (3); among the 1,862 participants who had had a previous myocardial infarction, there were significantly more deaths from fatal coronary heart disease in the -carotene group (10). The incidence of cardiovascular disease deaths was increased 26% in the CARET study (4); there was no difference in cardiovascular disease rates in the total population of the Physician’s Health Study (those with prior angina or coronary revascularizations, however, did seem to benefit) (5). In the ATBC study, -carotene had no effect on fatal coronary heart disease (11).
• Diabetes prevention
  • In the Physicians Health Study, -carotene supplementation for an average of 12 years had no effect on the risk of type II diabetes (12).
• Photosensitivity
  • Carotenoids can lessen photosensitivity caused by porphyrins by quenching excited species formed by the interaction of porphyrins with light. Both -carotene and canthaxanthin have been used to treat erythropoietic porphyria and other photosensitivity diseases; -carotene is preferable because canthaxanthin can cause a reversible retinopathy (13).
  • A recent study found that 25 mg mixed carotenoids (primarily -carotene) with or without vitamin E (500 IU RRR--tocopherol) daily for 3 months reduced ultraviolet-light-induced erythema (14).

[Outline]

• CClinical Trials
  • Cancer prevention
  • Pancreatic cancer
  • Skin cancer
  • Precancerous conditions
  • Cardiovascular disease prevention
  • Diabetes prevention
  • Photosensitivity

[ADT ] Letter Key

Adverse Reactions

• Dietary and supplemental carotenoids are generally safe because they are stored in fat cells and tissues. Most are nontoxic even at high doses. Combining -carotene and alcohol, however, can cause hepatotoxicity.
• Hypercarotenosis, a yellowish discoloration of the skin (including palms and soles, which differentiates it from jaundice) is a benign effect of high doses of carotenoids.
• Canthaxanthin can cause a reversible retinopathy.
• Anovulation and amenorrhea have been associated with carotenemia, but there is no evidence that carotenoids affect reproductive function (see questions and answers).

Drug Interactions

• -Carotene supplementation may reduce plasma levels of other carotenoids, but these interactions have not been well-delineated (15).
• In humans, studies have been mixed on whether carotenoids interfere with the metabolism of -tocopherol (15).
• Alcohol interacts with -carotene, resulting in hepatotoxicity (alcohol also appears to enhance the toxicity of vitamin A, while promoting vitamin A deficiency) (16). In baboons, ethanol delays blood clearance of -carotene (17).

Animal Toxicity

• -Carotene does not interfere with reproductive function in rats given up to 1,000 mg/kg orally per day. Two-year chronic toxicity studies have found no increased tumors in rats or mice; vacuolated cells with eccentric nuclei were noted in the livers of dogs and mice but not rats (18).

[Outline]

• AAdverse Reactions
• DDrug Interactions
• TAnimal Toxicity

[DFFL ] Letter Key

Deficiency Signs and Symptoms

• Carotenoids are not necessary if preformed vitamin A is present in the diet (see vitamin A).

Factors Decreasing Availability/Absorption

• Inadequate bile flow, lipid malabsorption, reduced gastric acidity, increased dietary intake (absorption efficiency decreases as intake increases), vitamin E supplementation, fiber (especially pectins), lack of fat in diet, olestra, incomplete release of carotenoids from food matrix. Studies are mixed on whether supplementation with -carotene decreases serum levels of other carotenoids (19).

Factors Increasing Availability/Absorption

Dietary intake

Laboratory Tests

Plasma concentrations, measured by high-pressure liquid chromatography (HPLC)

[Outline]

• DDeficiency Signs and Symptoms
• FFactors Decreasing Availability/Absorption
• FFactors Increasing Availability/Absorption
• LLaboratory Tests

There is no standard dose of carotenoids; doses used in clinical trials are described previously.

• What is the connection between carotenemia and amenorrhea?
• Isn’t it impossible to overdose on -carotene?
• Why has -carotene been so unsuccessful in clinical trials?

Q: What is the connection between carotenemia and amenorrhea?

A: Since 1971, sporadic reports of diet-induced carotenemia have been associated with menstrual dysfunction (20,21). This effect has not been noted in women receiving -carotene supplements for photosensitivity, even when hypercarotenemia is present (22). Almost all of these women with carotenemia and menstrual dysfunction were vegetarian; hypercarotenemia may be simply a marker for a vegetarian diet, which in turn is associated with increased fecal excretion and, thus, decreased blood levels of estradiol. The effect may be due to other compounds in carrots; rabbits that have been fed large amounts of carrots show diminished ovarian secretion of progesterone (23).

Q: Isn’t it impossible to overdose on -carotene?

A: Excess -carotene is deposited in fat and skin, causing harmless hypercarotenosis. Until recently, it was thought that even very high doses of -carotene were nontoxic. However, a primate study found hepatotoxicity when high doses of -carotene were combined with ethanol. One could say that high-dose -carotene supplements should not be used in alcoholics; I would go further and say that no one should use high-dose supplements. Given the amount of data on lack of benefit and possible risk, only those with photosensitivity diseases should consider -carotene supplementation.

Q: Why has -carotene been so unsuccessful in clinical trials?

A: The association of serum -carotene levels with decreased risk of cancer and heart disease may have been merely a marker for intake of carotenoids (or other protective factors in fruits and vegetables). One reason that supplementing with -carotene may have an adverse effect is that it may displace other dietary carotenoids. Maria Linder, PhD, author of Nutritional Biochemistry, has suggested that use of isolated -carotene may increase formation of oxidation products (24).

1. Olson JA. Carotenoids. In: Shils ME, Olson JA, Shike M et al, eds. Modern nutrition in health and disease, 9th ed. Baltimore: Williams & Wilkins, 1999:525–542.
2. Mayne ST. Beta-carotene, carotenoids, and disease prevention in humans. FASEB J 1996;10:690–701.
3. Heinonen OP, Albanes D, for 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. N Engl J Med 1994;330:1029–1035.
4. Omen GS, Goodman GE, Thornquist MD et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150–1155.
5. Hennekens CH, Buring JE, Manson JE et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145–1149.
6. Rautalahti MT, Virtamo JR, Taylor PR et al. The effects of supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer 1999;86:37–42.
7. GreenbergER, Baron JA, Stukel TA et al. A clinical trial of beta-carotene to prevent basal-cell and squamous-cell cancers of the skin. N Engl J Med 1990;323:789–795.
8. Giulano AR, Gapstur S. Can cervical dysplasia and cancer be prevented with nutrients? Nutr Rev 1998;56:9–16.
9. Mackerras D, Irwig L, Simpson JM et al. Randomized double-blind trial of beta-carotene and vitamin C in women with minor cervical abnormalities. Br J Cancer 1999;79:1448–1453.
10. Rapola JM, Virtamo J, Ripatti S et al. Randomised trial of -tocopherol and B-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet 1997;349:1715–17,20.
11. Virtamo J, Rapola JM, Ripatti S et al. Effect of vitamin E and beta-carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Int Med 1998;158:668–675.
12. Liu S, Ajani U, Chae C et al. Long-term -carotene supplementation and risk of type 2 diabetes mellitus. JAMA 1999;282:1073–1075.
13. Mathews-Roth MM. Carotenoids in erythropoietic protoporphyria and other photosensitivity diseases. Ann N Y Acad Sci 1993;691:127–138.
14. Stahl W, Heinrich U, Jungmann H et al. Carotenoids and carotenoids plus vitamin E protect against ultraviolet light-induced erythema in humans. Am J Clin Nutr 2000;71:795–798.
15. Palozza P. Prooxidant actions of carotenoids in biologic systems. Nutr Rev 1998;56:257–265.
16. Leo MA, Lieber CS. Alcohol, vitamin A, and -carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr 1999;69:1071–1085.
17. Leo MA, Kim C-I, Lowe N, Lieber C. Interaction of ethanol with B-carotene: delayed blood clearance and enhanced hepatotoxicity. Hepatology 1992;15:883–891.
18. Heywood R, Palmer AK, Gregson RL et al. The toxicity of beta-carotene. Toxicology 1985;36:91–100.
19. Van den Berg H. Carotenoid interactions. Nutr Rev 1999;157 (1):1–10.
20. Kemmann E, Pasquale SA, Skaf R. Amenorrhea associated with carotenemia. JAMA 1983;249:926–929.
21. Mathews-Roth MM. Amenorrhea associated with carotenemia. JAMA 1983;250:731.
22. Pan R M-D, Herrmann W. Carrot juice junkies and big bangs. Fertil Steril 1998;69:789.
23. Keenan DL, Dharmarajan AM, Zacur HA. Dietary carrot results in diminished ovarian progesterone secretion, whereas a metabolite, retinoic acid, stimulates progesterone secretion in the in vitro perfused rabbit ovary. Fertil Steril 1997;68:358–363.
24. Linder MC. (personal communication, 2001).