Many synthetic and naturally occurring phenols and catechols, such as butylated hydroxytoluene, butylated hydroxyanisole, alpha- tocopherol and plant flavonoids produces a variety of effects, including carcinogenesis, anti-carcinogenesis, tumor promotion and cytotoxicity. The elucidation of mechanisms by which these compounds exert their effects will lead to a better understanding of the biochemical events involved, and furnish valuable clues for the development of agents useful in cancer prevention and treatment. The biological effects elicited by phenolic compounds have been shown in several cases to be due to biotransformation processes, but little is known about the details of these relationships. Phenoxy radicals formed during enzymatic (or nonenzymatic) one- electron oxidations of phenols may form highly reactive peroxyquinols by combining with molecular oxygen. In general, these pathways have not been intensively studied because they do not represent quantitatively major metabolic processes, and because the resulting quinonoid species are usually too reactive to be observed. Recent studies with synthetic peroxyquinols confirmed the role of these species as metabolic intermediates in liver microsomes and isolated hepatocytes. Furthermore, they were shown to adversely affect biochemical parameters while exerting a considerably higher level of toxicity than their phenolic precursors.
The specific aims for the project are as follows. (1) Investigate mechanistic details of hemoprotein-peroxyquinol interactions. Preliminary work with cytochrome P-450 will be extended to other important hemoproteins. Detailed studies of the products generated and their pathways of formation will be conducted. The effects of peroxyquinol structure on the nature and the amounts of intermediates and products formed will provide data to test proposed mechanisms. (2) Determine the mechanistic basis for the effects of peroxyquinols on cellular biochemistry. Peroxyquinols of varying structures will be added to isolated hepatocytes and their effects on cell viability, thiols, NADPH, lipid peroxidation, and the generation of reactive oxygen species will be determined, as well as covalent binding to cellular protein. Attempts will be made to correlate the biochemical data with specific peroxidative pathways. (3) Investigate metabolic products and biochemical effects of alkylated phenols. The metabolism and biochemical effects of phenolic precursors of the peroxyquinols will be investigated in hepatocytes and subcellular fractions. This data will provide further information concerning the importance of peroxyquinol pathways to the biological effects of alkylated phenols.
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