Phenacetin and chlorzoxazone biotransformation in aging male Fischer 344 rats

The Journal of Pharmacy and Pharmacology
Jill S WarringtonLisa L von Moltke

Abstract

We evaluated the role of specific isoforms in the biotransformation of phenacetin and chlorzoxazone and examined the effect of age on these reactions using liver microsomes from Fischer 344 rats between 3 and 26 months of age. Using rat cDNA-expressed cytochrome P450 (CYP) enzymes, we found that phenacetin biotransformation was primarily mediated by CYP2C6 and CYP1A isoforms, while chlorzoxazone biotransformation was largely mediated by CYP2E1 and CYP1A1. Incubations with liver microsomes prepared from rats of varying ages demonstrated that both phenacetin and chlorzoxazone biotransformation declined with age. Metabolite formation rates in the old rats (25-26 months) were reduced by approximately 60-70% for these reactions. This study suggests that the activity of CYP2E and CYP1A enzymes decline with age in the rat liver. Also, the relative specificity of the index substrates phenacetin (for CYP1A2) and chlorzoxazone (for CYP2E1) in man appears not to be applicable in rats.

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Jan 27, 2004·The Journal of Pharmacology and Experimental Therapeutics·Jill S WarringtonLisa L von Moltke

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Citations

May 19, 2006·Rejuvenation Research·F MarottaP Marandola
Sep 6, 2007·The Journal of Toxicological Sciences·Kazuyuki HashimotoShuji Tsuda
Nov 26, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kayoko OhuraTeruko Imai
May 10, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Anne-Laure MinnYves Artur
Jan 1, 2015·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·Yasunobu AokiTakehiko Nohmi

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