Comparison of the effects of inducers of cytochrome P450 on Mongolian gerbil and rat hepatic microsomal monooxygenase activities

Abstract

1. Basal cytochrome P450 content (nmol/mg protein) was higher in gerbil (1.10 +/- 0.01) than in rat (0.81 +/- 0.05) hepatic microsomes. Pretreatment of gerbils with phenobarbitone and beta-naphthoflavone increased P450 contents by 200% and 60% respectively. 2. 7-Ethoxycoumarin O-deethylase, coumarin 7-hydroxylase and 4-nitrophenol hydroxylase activities were generally higher in gerbil liver microsomes, whereas erythromycin N-demethylase, and 7-ethoxyresorufin and 7-pentoxyresorufin O-dealkylase activities were higher in rat microsomes. Microsomal benzphetamine N-demethylase activities were similar in both species. 3. Induction of specific cytochrome P450 isozymes increased similar monooxygenase activities of rat and gerbil microsomes. Phenobarbitone, beta-naphthoflavone, isoniazid and pregnenolone 16 alpha-carbonitrile principally increased benzphetamine N-demethylase, 7-ethoxyresorufin O-deethylase, 4-nitrophenol hydroxylase and erythromycin N-demethylase activities respectively. 4. Constitutive 7-ethoxyresorufin and 7-pentoxyresorufin O-dealkylase activities were markedly lower in gerbil microsomes compared with rat microsomes, and pretreatment of gerbils with cytochrome P450 inducers did not significantly increase these activities. 5. Hepatic microsomal coumarin 7-hydroxylase activities were approximately 30-200 times greater (depending on the inducer) in the gerbil than in rat. The gerbil, due to is high coumarin 7-hydroxylase activity, would appear to be a more appropriate species than rat for investigations of coumarin metabolism and toxicity relevant to humans.