Substantial amounts of beta-carotene are being administered to thousands of volunteers in ongoing preventive studies and are being consumed by the general public in an uncontrolled undocumented fashion. Beta-carotene is being taken for its anti-cancer effects or as a precursor of (and substitute for) vitamin A, which has known intrinsic hepatotoxicity, exacerbated by ethanol. However, recent experimental studies and epidemiological observations in man revealed toxic interactions between ethanol and beta-carotene. Since moderate alcohol consumption is being advocated as possible health benefits, we determine such intake can adversely interact with beta-carotene supplementation. Established animal models in rats and nonhuman primates, as well as judicious clinical studies, will be used to determine the minimally effective dose of beta- carotene needed to restore hepatic vitamin A levels, whether this is affected by associated moderate alcohol consumption (1 or 2 drinks per day), whether beta-carotene, given in amounts commonly used at present, is influenced by moderate alcohol consumption in terms of absorption, disposition, and possible toxic manifestations, and whether the latter are exacerbated by beta-carotene beadlets. We will further ascertain the activity of the enzyme responsible for intestinal cleavage of beta-carotene is altered by chronic supplementation of beta-carotene and/or associated ethanol usage. Toxic manifestations will be assessed by measurements of circulating liver enzymes (AST, ALT) and of glutamic dehydrogenase (GDH), a marker of mitochondrial injury, as well as by ultrastructural changes in hepatic tissue. Additional experiments will be conducted to determine whether beta-carotene can attenuate the oxidant stress associated with alcohol (with or without iron), while avoiding toxic ethanol/beta-carotene interactions. Parameters of lipid peroxidation, such as F2-isoprostanes and 4-hydroxynonenal, determined by GC/MS will be assessed, Beta Carotene and other carotenoids will be measured by a state-of-the art HPLC method. Associated vitamin E changes will also be evaluated since beta-carotene may act as an antioxidant either directly (by trapping singlet-oxygen or other free radicals) or indirectly, by enhancing tissue and plasma, vitamin E. Possible synergism between beta-carotene and vitamin E supplementation will be evaluated. Ubiquinones 9, 10 (reduced and oxidized forms) shown to be affected earlier than the tocopherols in the plasma of humans exposed to oxidant stress, will also be measured by HPLC and electrochemical detection. The ultimate goal is to define the interactions between ethanol (especially moderate intake) with beta-carotene in terms of bioavailability and possible toxicity, to assess the advantages and possible disadvantages of beta-carotene substitution for vitamin A, and to formulate recommendations for optimal supplementation for that vast segment of our population drinking alcohol, albeit moderately.
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