Constitutive and induced hepatic microsomal cytochrome P-450 monooxygenase activities in male Fisher-344 and CD rats. A comparative study

Abstract

The hepatic microsomal mixed function monooxygenase system (MFO) is the major enzyme system responsible for the activation and deactivation of xenobiotics. This study was designed to compare the hepatic MFO system in Fischer-344 and CD (Sprague-Dawley) rats. Hepatic microsomes were prepared from control, phenobarbital (3 × 80 mg/kg)-, and 3-methylcholanthrene (3 × 20 mg/kg)-pretreated male F-344 and CD rats (49 days old). Both control and phenobarbital-treated F-344 rats had significantly lower microsomal epoxide hydratase activity than corresponding preparations from CD rats. In addition, the pattern of benzo( a)pyrene metabolism was significantly different between the strains. Microsomes from F-344 rats produced less dihydrodiols and quinones than the corresponding preparations from CD rats. The spectral characteristics of cytochrome P-450 in hepatic microsomes from both control and phenobarbital-treated F-344 rats were significantly different from those observed in CD rat hepatic microsomes. Specifically, the λ max for the reduced cytochrome P-450 CO complex occurred at a slightly longer wavelength and the reduced ETNC 430 455 nm peak ratios were larger by about 70%. No significant strain differences were detected in control rats or rats pretreated with either phenobarbital or 3-methylcholanthrene with regard to microsomal protein, benzphetamine- N-demethylase, NADPH-cytochrome c reductase, biphenyl-4-hydroxylase, biphenyl-2-hydroxylase, arylhydrocarbon hydroxylase, ethoxycoumarin- or ethoxyresorufin- O-deethylase activities. These results suggest that differences do exist in the in vitro hepatic microsomal metabolism of xenobiotics in these two strains of rats. These differences may be of importance with respect to the susceptibility of the two strains of rats to various toxic agents.