Lungs 3-carotene

Retinoids, isothiocyanates and tea polyphenols have been identified as possible chemopreventive agents for cancers of the lung and oral cavity. While a number of trials have been conducted with retinoids or (3-carotene, the results were ambiguous and the causes are still being debated. 

The a-tocopherol, P-carotene (ATBC) Cancer Prevention study was a randomised-controlled trial that tested the effects of daily doses of either 50 mg (50 lU) vitamin E (all-racemic a-tocopherol acetate), or 20 mg of P-carotene, or both with that of a placebo, in a population of more than 29,000 male smokers for 5-8 years. No reduction in lung cancer or major coronary events was observed with any of the treatments. What was more startling was the unexpected increases in risk of death from lung cancer and ischemic heart disease with P-carotene supplementation (ATBC Cancer Prevention Study Group, 1994). Increases in the risk of both lung cancer and cardiovascular disease mortality were also observed in the P-carotene and Retinol Efficacy Trial (CARET), which tested the effects of combined treatment with 30 mg/d P-carotene and retinyl pahnitate (25,000 lU/d) in 18,000 men and women with a history of cigarette smoking or occupational exposure to asbestos (Hennekens et al, 1996). 

ALPHA-TOCOPHEROL BETA-CAROTENE (ATBC) CANCER PREVENTION STUDY GROUP (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers , New Engl J Med, 330, 1029. 

It is well known that excessive intake of P-carotene may lead to carotenodermia (yellow skin), and it is undoubtedly the case that some carotenoid is directly lost via the skin or through photo-oxidation in the skin. As far as is known the carotenoids are not cytotoxic or genotoxic even at concentrations up to 10 times the normal plasma concentration which may cause carotenodermia. However, they are associated with amenorrhoea in girls who may be consuming bizarre diets and, in long-term supplementation studies, with an increase in lung cancer (The Alpha-tocopherol, Beta-carotene Cancer Prevention Study Group, 1994). 

OMENN G S, GOODMAN G E, THORNQUIST M D, BALMES J, CULLEN M R, GLASS A, KEOGH J P, MEYSKENS F L, VALANIS B, WILLIAMS J H, BARNHART S and HAMMAR S (1996) Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease. N EnglJ Med 1150-1155. 

Subsequent studies have confirmed that the reason for this discrepancy is that the rat is able to rapidly metabolise P-carotene to retinol in the intestine, through the action of intestinal dioxygenase. In contrast humans absorb P-carotene systemically such that plasma levels of P-carotene increase to levels not found in the rodent. A more appropriate animal model is the ferret, which shows a similar metabolism to humans. High levels of plasma P-carotene in the ferret induce the cellular transcription factors c-fos and c-jun, and squamous metaplasia is seen in the lung with or without exposure to cigarette smoke (SCF, 2000). Even after the investment of all these resources it has not been possible for the EU Scientific Committee on Food to set an ADI. 

Womens Health Study 50 mg/alternate days, 2.1 yr P-Carotene Lung cancer 0 38... 

Primary prevention trial (Alpha-Tocopherol, 20 mg/day, 5 to 8 yr P-Carotene Lung cancer -t 35... 

Placebo-controlled chemoprevention trial 30 mg/day carotene + 25,000 lU P-Carotene Lung cancer and total mortality + 36... 

Primary prevention trial (Physicians Health 20 mg/alternate days, 12 yr P-Carotene Lung cancer risk 0 37... 

Holick, C.N. et al., Dietary carotenoids, serum beta-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-carotene cohort study, Am. J. Epidemiol., 156, 536, 2002. 

Omenn, G.S. et al., Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial, J. Natl. Cancer Inst., 88, 1550, 1996. 

Palozza, P. et al., Dual role of beta-carotene in combination with cigarette smoke aqueous extract on the formation of mutagenic lipid peroxidation products in lung membranes dependence on pOj, Carcinogenesis, 2006. 

Liu, C., Russell, R.M., and Wang, X.D., Exposing ferrets to cigarette smoke and a pharmacological dose of beta-carotene supplementation enhance in vitro retinoic acid catabolism in lungs via induction of cytochrome P450 enzymes, J. Nutr., 133, 173, 2003. 

Sommerburg, O. et al.. Cytotoxic and genotoxic effects due to beta-carotene cleavage products possibly formed in inflamed lung tissue. Free Rad. Biol. Med., 36, S56, 2004. 

Yeh, S.L. and Hu, M.L., Oxidized [beta]-carotene inhibits gap junction intercellular communication in the human lung adenocarcinoma cell line A549, Food Chem. Toxicol., 41, 1677, 2003. 

Lutein has some structural similarities to P-carotene, reported to enhance the development of lung cancer when given in supplement form to heavy smokers. The available data indicate that lutein in food would not be expected to have this effect. The committee was unable to assess whether lutein in the form of supplements would produce the reported effect in heavy smokers. 

Supplementation is not without risk. For example, beta carotene supplementation in smokers may increase the risk of developing lung cancer.23 At this time, it is not clear from the... 

The interaction of carotenoids with cigarette smoke has become a subject of interest since the results of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Group 1994 (ATBC) and CARET (Omenn et al. 1996) studies were released. P-Carotene has been hypothesized to promote lung carcinogenesis by acting as a prooxidant in the smoke-exposed lung. Thus, the autoxidation of P-carotene in the presence of cigarette smoke was studied in model systems (toluene) (Baker et al. 1999). The major product was identified as 4-nitro-P-carotene, but apocarotenals and P-carotene epoxides were also encountered. 

A somewhat related situation can be used to explain the well-publicized lung-cancer inducing effects of P-carotene in heavy smokers. This subpopulation will have low vitamin C levels and hence damage due to smoke components, such as N02 can produce P-CAR which will reach the lung and initiate damage. In nonsmokers, the vitamin C (or other water-soluble antioxidant) is likely to be present in sufficient concentration to preclude this damaging process. Indeed, this speculation has been promoted by the American Chemical Society as the subject of a press release in 1997 (Bohm et al. 1997). 

Omenn, GS, Goodman, GE, Thomquist, MD, Balmes, J, Cullen, MR, Glass, A, Keogh, JP, Meyskens, FL, Valanis, B, Williams, JH, Barnhart, S, Cherniack, MG, Brodkin, CA, and Harnmar, S, 1996. Risk factors for lung cancer and for intervention effects in CARET, the beta-carotene and retinol efficacy trial. J Natl Cancer Inst 88, 1550-1559. 

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