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Pure Appl. Chem., 2002, Vol. 74, No. 8, pp. 1461-1467

Beta-carotene and lung cancer

Robert M. Russell

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA

Does beta-carotene increase, rather than decrease, human lung cancer rates? A large body of observational epidemiologic study has demonstrated that individuals who eat more fruits and vegetables rich in carotenoids and/or who have higher levels of serum beta-carotene have a lower risk of cancer, particularly lung cancer. This inverse relationship has been particularly strong in lung cancer patients with a history of heavy smoking. However, there is contradictory evidence from recent human intervention studies using beta-carotene supplements (20­30 mg per day). An increase in risk of lung cancer among smokers who took beta-carotene supplements was reported in the Alpha Tocopherol, Beta-carotene Cancer Prevention (ATBC) Trial and among smokers and asbestos-exposed workers in the Beta-Carotene and Retinol Efficiency Trial (CARET), but not among male physicians in the United States in the Physicians Health Study (only 11 % of whom were current smokers). Whether there is a true hazard associated with beta-carotene has been evaluated in control studies using the ferret. This animal mimics the human tissue metabolism of beta-carotene, and has been used for studies of tobacco smoking and inhalation toxicology. In the first study, ferrets were given a high-dose beta-carotene supplement equivalent to 30 mg per day in humans, and exposed cigarette smoke or both for six months. A strong proliferative response in lung tissue and squamous metaplasia were observed in all beta-carotene-supplemented animals, and this response was enhanced by exposure to tobacco smoke. When compared to the control group, beta-carotene-supplemented animals (with or without smoke exposure) had statistically significantly lower concentrations of retinoic acid in lung tissue, and they exhibited reductions in RAR-beta gene expression (a tumor suppressor gene). Further, ferrets given a high-dose beta-carotene supplement and exposed to tobacco smoke had fourfold elevated expressions of c-jun and c-fos genes. In a second study, ferrets were given either physiological- or pharmacologic-dose beta-carotene supplementations, which were equivalent to 6 mg vs. 30 mg per day in humans, respectively. The animals were exposed to cigarette smoke for six months. The retinoic acid concentration and RAR beta-gene expression were reduced in the lung tissues, whereas the expression of AP1, cyclin D1, and proliferative cell nuclear antigen were greater in the high-dose, beta-carotene-supplemented animals with or without smoke, as well as the smoke-exposed, low-dose, beta-carotene-supplemented animalsbut not in the low-dose, beta-carotene-supplemented animals alone, as compared with the control group. Squamous metaplasia was only observed in the lung tissues of high-dose, beta-carotene exposed groups with or without smoke (but not the low-dose beta-carotene plus smoke group, the low-dose beta-carotene-supplemented group, or the control group). These data show that in contrast with the pharmacologic dose of beta-carotene, a physiologic dose of beta-carotene in smoke-exposed ferrets has no detrimental effectand, in fact, may afford weak protection against lung damage induced by cigarette smoke.
Further studies from our laboratory have revealed an instability of the beta-carotene molecule in the lungs of cigarette smoke-exposed ferrets. Oxidized beta-carotene metabolites may play a role in lung carcinogenesis: by inducing carcinogen-bioactivating enzymes, facilitating the binding of metabolites of benz[a]pyrene to DNA, enhancing retinoic acid metabolism by P450 enzyme induction with subsequent down-regulation of RAR-beta, and acting as pro-oxidants, causing damage to DNA. Ferret studies under highly controlled experimental conditions using high- and low-dose beta-carotene in the presence of alpha tocopherol and ascorbic acid (thereby stabilizing the beta-carotene molecule) showed protective effects against smoke-induced lung squamous metaplasia in ferrets.