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Depression of the Hepatic Cytochrome P-450 Monooxygenase System by Treatment of Mice with the Antineoplastic Agent 5-Azacytidine¹

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

The effects of 5-azacytidine (5-AC) administration on the hepatic cytochrome P-450 systems of mice were studied. A single i.p. dose of 5-AC (25 mg/kg) to male Swiss-Webster mice caused about a 50% depression of microsomal cytochromes P-450 and b₅ and of ethylmorphine N-demethylase and ethoxycoumarin O-deethylase activities. Depression was greatest 24 h after treatment; by 48 to 72 h, cytochromes and drug metabolism had returned to near control values. Reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase activity was also depressed by 5-AC, whereas reduced nicotinamide adenine dinucleotide-cytochrome c reductase was not. Incubation of 5-AC with microsomes produced no effect on drug metabolism. The prolongation of hexobarbital sleeping time by 5-AC showed that drug metabolism is also impaired by 5-AC in vivo. These studies may have important clinical implications when certain drugs are coadministered with 5-AC.

¹ This investigation was supported by USPHS Grant GM27780. A preliminary report of this work was presented at the 1983 Annual Meeting of the American Society of Pharmacology and Experimental Therapeutics, Philadelphia, PA (45).

² To whom requests for reprints should be addressed.

Received 9/18/84. Revised 12/14/84. Accepted 12/28/84.

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