Regulation of constitutive rat hepatic cytochromes P450 by 3-methylcholanthrene

1. Induction of cytochrome P450 (CYP) enzymes of the CYP1A subfamily by aromatic hydrocarbons such as 3-methylcholanthrene (MC) is accompanied by down-regulation of other CYPs that are expressed constitutively in rat liver. 2. We examined the time-course of the effects of MC on the expression of CYP2C11 and 3A2 in the liver of male rats at the catalytic activity, apoprotein and mRNA levels. 3. A single intraperitoneal dose of MC (50 mg/kg) caused an increase in total hepatic microsomal CYP and haem content, and a marked induction of CYP1A1 catalytic activity (7-ethoxyresorufin O-deethylase) and apoprotein. The activity of NADPH-cytochrome P450 reductase was not altered. 4. MC treatment decreased CYP2C11 and 3A catalytic activity (testosterone 16 alpha- and 6 beta-hydroxylase respectively) and apoprotein, and there was a trend for suppression of 2C11 and 3A2 mRNA. Following this initial down-regulation, CYP2C11 catalytic activity and 3A catalytic activity and apoprotein were elevated above control levels. Although CYP2C11 and 3A2 mRNA levels showed a similar trend, these effects did not achieve statistical significance. 5. CYP2C11 and 3A2 appear to be regulated by MC at a pre-translational level. CYP2C11 suppression will serve as a valuable model for study on the mechanisms by which aromatic hydrocarbons act to negatively influence gene expression.