Health Care Professional Information

Clinical Summary

A natural pigment synthesized by plants, beta-carotene is used as an antioxidant and an immunostimulant, and to prevent or treat cancer, HIV, heart disease, and leukoplakia. Beta-carotene, along with alpha-carotene and beta-cryptoxanthin, can be converted to retinol and is classified as a provitamin A carotenoid. Supplementation with beta-carotene does not increase overall vitamin A levels or lead to vitamin A toxicity.
Animal studies show that beta-carotene promotes the development of pulmonary adenocarcinoma via increased cAMP signaling (29).

Available data concerning beta-carotene supplementation for HIV-positive patients and its effects on CD4 counts (10) as well as cardiovascular disease are conflicting. A meta-analysis of eight randomized trials demonstrated a small but significant increase in all-cause mortality and cardiovascular death for the beta-carotene arm over placebo (11), whereas other studies have reported no benefits of beta-carotene supplementation on cardiovascular disease (12) or its risk factors (13).
Consistent associations between serum beta-carotene levels and risk of developing type 2 diabetes are also lacking (14)(15). One study reported that serum beta-carotene was inversely associated with the incidence of cataract formation (16).
Long-term beta-carotene supplementation may increase cognitive function (17).

Epidemiological associations between beta-carotene and cancer risk are conflicting. Whereas high dietary beta-carotene intake was associated with reduced risk of cervical cancer (1), high serum levels were also associated with increased risk for aggressive prostate cancer (2) but decreased the risk of aggressive urothelial cell carcinoma (32). In addition, studies of beta-carotene supplementation and chemoprevention for cancer are inconsistent. Studies show that consumption of beta carotene, vitamins A, C, fruits and vegetables does not influence the risk of renal cell carcinoma (31). A review of 14 clinical trials shows that supplementation with antioxidants, beta-carotene and vitamins A, C, and E, does not prevent gastrointestinal cancer, and that  beta-carotene may actually increase overall mortality (3) (4). Data from large, multicenter trials suggest that beta-carotene supplementation may not lower the risk of prostate cancer (5) (6), and in male smokers over the age 40, it may increase lung cancer incidence (7) (30).
Beta-carotene supplementation especially when combined with cigarette smoking may also reduce the efficacy of cancer therapies, resulting in increased recurrence and mortality (8).
One large-scale cohort study in the Netherlands suggests alcohol consumption has a negative effect on the chemopreventive property of beta-carotene (9).

The U.S. Preventive Services Task Force (USPSTF) recommends against beta-carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer (33).

Food Sources

Deep yellow and orange fruits (apricots, cantaloupe, papaya), squash, carrots, sweet potatoes, pumpkin, leafy greens, and broccoli (18)(19)

Purported Uses
  • Cancer prevention
  • Cardiovascular disease
  • Cataracts
  • HIV and AIDS
  • Immunostimulation
  • Macular degeneration
  • Oral leukoplakia
Mechanism of Action

Beta-carotene has strong antioxidant effects. It protects lipid peroxidation and provitamin-A activity, thereby preventing oxidative damage (34). It was also shown to alleviate the severity of ulcerative colitis in mice by modulating several molecular targets including nuclear factor-kappa B, cyclooxygenase-2, interleukin 17, and connective tissue growth factor (35).

In other studies, beta-carotene reduced cell growth and induced apoptosis in a variety of cancer cell lines possibly through caveolin-1 expression (20). In vivo studies suggest that beta-carotene induces glutathione production (21). Beta-carotene may enhance macrophage function and natural killer (NK) cell cytotoxicity and increase T-helper lymphocyte counts. However, recent clinical studies suggest that beta-carotene can increase cancer risk, and in vitro studies have shown that beta-carotene induces angiogenic gene expression in human umbilical vein endothelial cells (HUVEC) as well as HUVEC migration (22). Furthermore, beta carotene stimulated cellular proliferation in a pancreatic ductal adenocarcinoma cell line (23) and in lung cancer cells (24).

Pharmacokinetics

Absorption
Intestinal absorption of carotenoids, including beta-carotene, is facilitated by the formation of bile acid micelles. The presence of fat in the small intestine stimulates the secretion of bile acids from the gall bladder and improves the absorption of carotenoids by increasing the size and stability of the micelles, thus allowing more carotenoids to be solubilized. Beta-carotene may be absorbed intact or cleaved to form vitamin A. Source, dose, and presence of other carotenoids affect its bioavailability.
Distribution
The concentration of beta-carotene in human serum and tissues is highly variable and depends on food sources, efficiency of absorption, and amount of fat in the diet. Beta-carotene is transported in the blood primarily by low-density lipoproteins. The serum concentration of carotenoids after a single dose peaks at 24-48 hours post dose. The earliest postprandial serum appearance of carotenoids is in the chylomicron fraction. Beta-carotene is primarily stored in adipose tissue and liver.
Metabolism/Excretion
Beta-carotene may be cleaved to form vitamin A while being absorbed from the stomach. Cleavage is accomplished either by the intestinal mucosal enzyme beta-carotene 15-15' dioxygenase or by non-central cleavage mechanisms. The extent of conversion of a highly bioavailable source of dietary beta-carotene to vitamin A in humans has been shown to be between 60-75%, with an additional 15% of the beta-carotene absorbed intact. Non-central cleavage of carotenoids yields a wide variety of metabolic products, including aldehydes, acid, alcohol, and epoxide derivatives. It is assumed that beta-carotene is eliminated in bile and urine.
(27)

Adverse Reactions

Toxicity: Carotenodermia is a harmless but clearly documented effect of high carotenoid intake. A yellowish discoloration of the skin resulted following chronic intake of food and supplements containing large amounts of carotenoids (36) (37) (38).

Herb-Drug Interactions

Ethanol: Hepatotoxic effects of ethanol may be potentiated by high doses of beta-carotene. One large-scale cohort study in the Netherlands suggests alcohol consumption has a negative effect on the chemopreventive property of beta-carotene.
(9)(19)

Literature Summary and Critique

Grodstein F, et al. A randomized trial of beta carotene supplementation and cognitive function in men: the Physicians' Health Study II. Arch Intern Med. Nov 12 2007;167(20):2184-2190.
The effects of short-term or long-term beta-carotene supplementation (50 mg every other day) on cognitive function were determined in participants from the Physicians' Health Study II. Participants (men >65 years) were analyzed for general cognition, verbal memory, and category fluency. Although participants receiving beta-carotene supplementation for a mean of 1 year did not show any improvements in cognitive function, those in the long-term group (mean duration of 18 years) had increased cognitive performance compared to the placebo-control group. Due to the possible health risks associated with beta-carotene supplementation, further studies are required to determine the risk-to-benefit ratio of beta-carotene supplementation.

Arnlov J, et al. Serum and dietary beta-carotene and alpha-tocopherol and incidence of type 2 diabetes mellitus in a community-based study of Swedish men: report from the Uppsala Longitudinal Study of Adult Men (ULSAM) study. Diabetologia. Nov 5 2008.
To determine if serum levels or dietary intake of beta-carotene influence the incidence of type 2 diabetes, 846 non-diabetic men (50 years of age) were followed up to 27 years in this longitudinal study. Participants with the highest serum levels of beta-carotene had reduced risk of developing type 2 diabetes. Conversely, impaired insulin sensitivity was associated with low serum beta-carotene. Further studies are required to determine if beta-carotene is associated with the incidence of type 2 diabetes in women.

Satia JA, Littman A, Slatore CG, Galanko JA, White E. Long-term use of beta-carotene, retinol, lycopene, and lutein supplements and lung cancer risk: results from the VITamins And Lifestyle (VITAL) study. Am J Epidemiol. 2009 Apr 1;169(7):815-28.
This study was conducted to determine associations of supplemental beta-carotene, retinol, vitamin A, lutein, and lycopene with lung cancer risk in 77,126 subjects, aged 50-76 years, in the VITamins And Lifestyle (VITAL) cohort Study in Washington State between 2000 and 2002. Participants completed a 24-page questionnaire about supplement use including duration, frequency, and dose during the previous 10 years from multivitamins and individual supplements/mixtures. Five hundred and twenty-one cases of incident lung cancers were identified. Longer duration of beta-carotene, retinol and lutein supplements was associated wtih statistically significant higher risk of total lung cancer. Gender or smoking status did not affect the risk.
The authors concluded that long-term supplementation with beta-carotene, retinol, and lutein should not be recommended for preventing lung cancer, particularly among smokers.

Dosage (Inside MSKCC Only)
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References
  1. Ghosh C, Baker JA, Moysich KB, et al. Dietary intakes of selected nutrients and food groups and risk of cervical cancer. Nutr Cancer. May-Jun 2008;60(3):331-341.
  2. Peters U, Leitzmann MF, Chatterjee N, et al. Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev. May 2007;16(5):962-968.
  3. Bjelakovic G, Nikolova D, Simonetti RG, et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. Oct 2-8 2004;364(9441):1219-1228.
  4. Bjelakovic G, Nikolova D, Simonetti RG, et al. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database Syst Rev. 2008(3):CD004183.
  5. Kirsh VA, Hayes RB, Mayne ST, et al. Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk. J Natl Cancer Inst. Feb 15 2006;98(4):245-254.
  6. Ambrosini GL, de Klerk NH, Fritschi L, et al. Fruit, vegetable, vitamin A intakes, and prostate cancer risk. Prostate Cancer Prostatic Dis. 2008;11(1):61-66.
  7. 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. N Engl J Med. Apr 14 1994;330(15):1029-1035.
  8. Meyer F, Bairati I, Fortin A, et al. Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients. Int J Cancer. Apr 1 2008;122(7):1679-1683.
  9. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. Jun 1999;69(6):1071-1085.
  10. Coodley GO, Coodley MK, Lusk R, et al. Beta-carotene in HIV infection: an extended evaluation. AIDS. Aug 1996;10(9):967-973.
  11. Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. Jun 14 2003;361(9374):2017-2023.
  12. 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. May 2 1996;334(18):1145-1149.
  13. Wang L, Gaziano JM, Norkus EP, et al. Associations of plasma carotenoids with risk factors and biomarkers related to cardiovascular disease in middle-aged and older women. Am J Clin Nutr. Sep 2008;88(3):747-754.
  14. Arnlov J, Zethelius B, Riserus U, et al. Serum and dietary beta-carotene and alpha-tocopherol and incidence of type 2 diabetes mellitus in a community-based study of Swedish men: report from the Uppsala Longitudinal Study of Adult Men (ULSAM) study. Diabetologia. Nov 5 2008.
  15. Kataja-Tuomola M, Sundell JR, Mannisto S, et al. Effect of alpha-tocopherol and beta-carotene supplementation on the incidence of type 2 diabetes. Diabetologia. Jan 2008;51(1):47-53.
  16. Dherani M, Murthy GV, Gupta SK, et al. Blood levels of vitamin C, carotenoids and retinol are inversely associated with cataract in a North Indian population. Invest Ophthalmol Vis Sci. Aug 2008;49(8):3328-3335.
  17. Grodstein F, Kang JH, Glynn RJ, et al. A randomized trial of beta carotene supplementation and cognitive function in men: the Physicians' Health Study II. Arch Intern Med. Nov 12 2007;167(20):2184-2190.
  18. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington D.C.: National Academy Press; 2000.
  19. Schuurman AG, Goldbohm RA, Brants HA, et al.A prospective cohort study on intake of retinol, vitamins C and E, and carotenoids and prostate cancer risk (Netherlands). Cancer Causes Control. Aug 2002;13(6):573-582.
  20. Palozza P, Sestito R, Picci N, et al. The sensitivity to beta-carotene growth-inhibitory and proapoptotic effects is regulated by caveolin-1 expression in human colon and prostate cancer cells. Carcinogenesis. Nov 2008;29(11):2153-2161.
  21. Takeda S, Bando N, Yamanishi R. Ingested beta-carotene enhances glutathione level and up-regulates the activity of cysteine cathepsin in murine splenocytes. Biosci Biotechnol Biochem. Jun 2008;72(6):1595-1600.
  22. Kiec-Wilk B, Polus A, Mikolajczyk M, et al. Beta-carotene and arachidonic acid induced DNA methylation and the regulation of pro-chemotactic activity of endothelial cells and its progenitors. J Physiol Pharmacol. Dec 2007;58(4):757-766.
  23. Al-Wadei HA, Majidi M, Tsao MS, et al. Low concentrations of beta-carotene stimulate the proliferation of human pancreatic duct epithelial cells in a PKA-dependent manner. Cancer Genomics Proteomics. Jan-Feb 2007;4(1):35-42.
  24. Al-Wadei HA, Takahashi T, Schuller HM. Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by beta-carotene via activation of cAMP, PKA, CREB and ERK1/2. Int J Cancer. Mar 15 2006;118(6):1370-1380.
  25. Zhang LX, Cooney RV, Bertram JS.Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive action. Carcinogenesis. Nov 1991;12(11):2109-2114.
  26. Brody T. Nutritional Biochemistry. San Diego (CA): Academic Press; 1999.
  27. Nierenberg DW, Stukel TA, Baron JA, et al. Determinants of increase in plasma concentration of beta-carotene after chronic oral supplementation. The Skin Cancer Prevention Study Group. Am J Clin Nutr. Jun 1991;53(6):1443-1449.
  28. Pronsky ZM. Power's and Moore's Food-Medication Interactions. 11th ed. Pottstown (PA): Food Medication Interactions; 2000.
  29. Al-Wadei HA, Schuller HM. beta-Carotene promotes the development of NNK-induced small airway-derived lung adenocarcinoma. Eur J Cancer. 2009 May;45(7):1257-64.
  30. Satia JA, Littman A, Slatore CG, Galanko JA, White E. Long-term use of beta-carotene, retinol, lycopene, and lutein supplements and lung cancer risk: results from the VITamins And Lifestyle (VITAL) study. Am J Epidemiol. 2009 Apr 1;169(7):815-28.
  31. Bertoia M, Albanes D, Mayne ST, et al. No association between fruit, vegetables, antioxidant nutrients and risk of renal cell carcinoma. Int J Cancer. 2010 Mar 15;126(6):1504-12.
  32. Ros MM, Bueno-de-Mesquita HB, Kampman E, et al. Plasma carotenoids and vitamin C concentrations and risk of urothelial cell carcinoma in the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr. 2012 Oct;96(4):902-10.
  33. Moyer VA; U.S. Preventive Services Task Force. Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: U.S. Preventive services Task Force recommendation statement. Ann Intern Med. 2014 Apr 15;160(8):558-64.
  34. Zhang PY, Xu X, Li XC. Cardiovascular diseases: oxidative damage and antioxidant protection. Eur Rev Med Pharmacol Sci. 2014 Oct;18(20):3091-6.
  35. Trivedi PP, Jena GB. Mechanistic insight into beta-carotene-mediated protection against ulcerative colitis-associated local and systemic damage in mice. Eur J Nutr. 2014 Jul 30. [Epub ahead of print]
  36. Boere IA, Hoskam JA. Yellow discolouration. Neth J Med. 2006 Feb;64(2):56-7.
  37. Sansone RA, Sansone LA. Carrot man: a case of excessive beta-carotene ingestion. Int J Eat Disord. 2012 Sep;45(6):816-8.
  38. Santos VM, Camilo AG, Souza LA, Souza DW, Marinho CS, Monteiro LM. A woman with treated breast cancer, recent neurological symptoms and xanthoderma. Acta Med Iran. 2013 Apr 6;51(3):195-8.

Consumer Information

How It Works

Bottom Line: Beta-carotene is not effective in treating heart disease, cancer, or HIV or preventing cataracts or macular degeneration.

Beta-carotene is an antioxidant that is found in yellow and orange fruits, such as apricots, cantaloupe, and papaya, as well as squash, carrots, sweet potatoes, pumpkin, leafy greens, and broccoli. Although scientists have proposed a number of mechanisms by which beta-carotene obtained through a healthy diet may prevent cancer, current evidence does not support supplementation.

 

 

 

 

Purported Uses
  • As an antioxidant
    Several studies support this use.
  • To prevent cancer
    Several large and well-designed clinical trials do not support the use of beta carotene supplements for preventing cancer. In fact, high beta-carotene intake has been linked to higher risk of lung cancer in male smokers and aggressive prostate cancer. (This does not necessarily apply to beta carotene obtained from the diet. Beta carotene may act in conjunction with other phytochemicals in fruits and vegetables).
  • To prevent and treat heart disease
    Several large and well-designed clinical trials and population studies show that taking beta-carotene supplements does not reduce the risk of myocardial infarction (heart attack), angina, or coronary artery disease. In fact, a review of clinical trials showed that beta-carotene was associated with a small increase in overall death as well as death to cardiovascular disease.
  • To prevent cataracts
    Clinical trials generally have shown that taking beta-carotene supplements does not reduce the risk of developing cataracts, but a small clinical study found that amounts of beta-carotene in the blood were associated with decreased cataracts, indicating that beta-carotene obtained from the diet, but not supplements may be helpful.
  • To treat HIV and AIDS
    Although a few small studies suggested that beta-carotene supplements could increase CD4 cell counts, recent clinical trials have not been able to replicate these results.
  • To stimulate the immune system
    Some laboratory experiments show that beta-carotene stimulates certain aspects of the immune system, but it is not certain that this effect occurs in the human body. No clinical trials have tested this use in healthy volunteers.
  • To prevent and treat macular degeneration
    One clinical trial suggested that taking an antioxidant supplement plus zinc reduces the risk of macular degeneration, but it is not clear whether beta-carotene, or any of the other antioxidants in this supplement, were responsible for these effects.
  • To treat oral leukoplakia
    Several clinical trials have shown that beta-carotene supplementation can induce remission of oral leukoplakia, a pre-cancerous lesion in the mouth.
  • To treat type 2 diabetes
    One clinical study found that high serum beta-carotene levels decreased risk of developing type 2 diabetes, but another study found that beta-carotene supplements did not reduce the risk for type 2 diabetes. Further studies of dietary beta-carotene are needed.
  • To improve cognition
    Results from a clinical trial suggest that long-term supplementation with beta-carotene may improve cognition; however, because of the possible health risks associated with beta-carotene supplementation, further studies are needed to determine if dietary beta-carotene could also improve cognition.
Research Evidence

Cancer and Heart Disease
The Physicians Health Study (a long-term study of male physicians age 40 - 84) examined the relationship between taking beta-carotene supplements and development of cancer or heart disease. Physicians were randomly split into four groups, and received 1) aspirin plus beta-carotene, 2) aspirin plus placebo pill, 3) beta-carotene plus placebo pill, or 4) two placebo pills, taken every other day. A total of 11,036 men took beta-carotene only and 11,035 men took a placebo. After 12 years, analysis showed that beta-carotene supplementation did not increase or decrease the risk of developing cancer or heart disease. Because women were not included in this study, these results might not apply to women.

This study was conducted to determine associations of supplemental beta-carotene, retinol, vitamin A, lutein, and lycopene with lung cancer risk in 77,126 subjects, aged 50-76 years, in the VITamins And Lifestyle (VITAL) cohort Study in Washington State between 2000 and 2002. Participants completed a 24-page questionnaire about supplement use including duration, frequency, and dose during the previous 10 years from multivitamins and individual supplements/mixtures. Five hundred and twenty-one cases of incident lung cancers were identified. Longer duration of beta-carotene, retinol and lutein supplements was associated wtih statistically significant higher risk of total lung cancer. Gender or smoking status did not affect the risk. 

Type 2 Diabetes
In a clinical trial of 846 non-diabetic men (50 years of age), participants were followed for 27 years to see if beta-carotene levels were related to risk of type 2 diabetes. Men with the highest serum levels of beta-carotene had reduced risk of type 2 diabetes. More studies are needed to see if these effects are the same in women.

Do Not Take If
  • You regularly consume alcohol (Alcohol may reduce its effects, and high doses of beta-carotene can increase the toxic effects that alcohol has on the liver.)
Side Effects
  • Prolonged intake of high doses of beta-carotene can lead to carotenodermia, a harmless yellowish discoloration of the skin.
Special Point
  • In general, high dietary intake of fruit and vegetables is associated with reduced risks of cancer and heart disease. Although beta-carotene supplements do not appear to prevent or effectively treat either of these diseases, beta-carotene obtained from the diet may be more beneficial. This is because it may interact with other phytochemicals in fruits and vegetables and have a greater effect on the body than do supplements alone.
E-mail your questions and comments to aboutherbs@mskcc.org.