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Decreased NADH-Oxidoreductase Activities as an Early Response in Rat Liver to the Carcinogen 2-Acetylaminofluorene¹

Departments of Biological Sciences [I. S., W. C. M., F. L. C., R. B., W. L. E., D. J. M.] and Medicinal Chemistry and Pharmacognosy [R.L. V., P. F.H., D. J. M.], and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907

Reduced nicotinamide adenine dinucleotide (NADH):ferricyanide reductase and DT-diaphorase specific activity in total homogenates of rat liver are markedly decreased as a very early biochemical event of hepatocarcinogenesis induced by the carcinogen 2-acetylaminofluroene (AAF). A 50 to 75% decrease in NADH:ferricyanide reductase was observed after 1 day of AAF (0.025% in the diet) feeding and persisted throughout a 7-week continuum of AAF administration. Carcinogen added directly to cell extracts had no effect. Similar results were obtained with single injections of either AAF or diethylnitrosamine. Xanthine dehydrogenase was also reduced in liver following AAF administration to nearly the same extent as NADH:ferricyanide reductase and DT-diaphorase. Total NADH;cytochrome c reductase and mitochondrial activity as estimated from succinic dehydrogenase were not affected by carcinogen administration relative to basal dietary controls. The reduced nicotinamide adenine dinucleotide phosphate:cytochrome c reductase that functions in drug detoxification was elevated. With livers of animals fed 4-acetamidophenol, a hepatotoxin chemically related to AAF, small decreases were noted in NADH:ferricyanide reductase, but not in xanthine dehydrogenase nor in DT-diaphorase. Initial lowering of these activities in the livers of the carcinogen-treated animals is preceded by or concomitant with a reduction in the levels of extramitochondrial pyridine nucleotides known from other studies to result from DNA damage.

¹ Work supported in part by Grants CA 18801 and CA 33441 from the NIH.

² Present address: Department of Chemistry, Indiana University, Bloomington, IN 47401.

³ To whom requests for reprints should be addressed.

Received 11/28/83. Accepted 9/27/84.