Why Did PCarotene Supplementation Increase Lung Cancer Risk in the ATBC and Caret Studies

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It is not yet known why high-dose p-carotene supplementation significantly increased the risk of lung cancer in smokers and other high-risk individuals, but a number of in vitro and in vivo studies published since those surprising results were made public offer some insight into possible mechanisms. In humans, p-carotene from supplements is much more readily absorbed than p-carotene from fruits and vegetables, resulting in plasma and tissue p-carotene levels many times higher than could be achieved by a carotenoid-rich diet.207 The ferret, unlike most rodents, is an appropriate species for modeling the effects of p-carotene supplementation and cigarette smoke exposure because tissue accumulation of p-carotene and lung pathology in response to tobacco exposure in ferrets is similar to that of humans.208 In ferrets, the presence of high concentrations of p-carotene in lung tissue results in increased formation of oxidative metabolites of p-carotene.209 These oxidative metabolites could promote carcinogenesis in the lung by inducing cytochrome P450 enzymes that bioactivate procarcinogens in cigarette smoke,210211 enhancing DNA

oio ono binding of benzo[a]pyrene metabolites, or altering retinoid signaling. In the CARET study, the increased risk of lung cancer was limited to current smokers.213 All of the participants were smokers in the ATBC study, but the effect of p-carotene was stronger in those who smoked at least 20 cigarettes daily.214 Alcohol use is also known to increase cytochrome P450 activity, and heavier alcohol use appeared to increase the effect of p-carotene supplementation on lung cancer risk in the ATBC and the CARET studies.213214 The lung-cancer-promoting effects associated with p-carotene supplementation in the ATBC and CARET studies may also have been dose related, which would explain the discrepancy between these intervention trials and the consistent inverse associations between dietary p-carotene consumption and lung cancer risk. When ferrets were given a dose of p-carotene equivalent to a human dose of 30mg/d, retinoid signaling in lung tissue was diminished and lung cell proliferation was increased.215 These potentially procarcinogenic changes were enhanced by cigarette smoke exposure. In contrast, these effects were not observed when ferrets were given a dose of p-carotene equivalent to a human dose of 6mg/d (the amount supplied by five to nine servings of fruits and vegetables). In fact, cigarette smoke-induced lung damage (squamous metaplasia) was slightly decreased. The lungs of cigarette smokers have been called a "free radical-rich, antioxidant-poor environment."208 Cigarette smokers have significantly lower plasma vitamin C concentrations than nonsmokers with equal vitamin C intakes,216 as do nonsmokers exposed to environmental tobacco smoke.217 Studies in vitro suggest that vitamin C can reduce the p-carotene radical back to pcarotene,218 potentially decreasing the formation of its oxidative metabolites. Vitamin E may also stabilize p-carotene and prevent the formation of excentric cleavage products known as apocarotenals.219 Apo-carotenals can be further oxidized to their corresponding retinoic acids. The biological activities of apo-carotenal metabolites have not been well characterized, but there is some evidence that they differ from those of retinoic acid.24209 Thus, high concentrations of p-

carotene along with relative deficiencies of vitamin C and possibly vitamin E in an oxidizing environment may also have contributed to an increased risk of lung cancer.

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