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.
Jones
E J
EJ
Department of Pharmacology, University of Toronto, Ontario, Canada.
Riddick
D S
DS
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002384:Catalysis; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006418:Heme / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*
D018336:Receptors, Aryl Hydrocarbon; D006418:Heme; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D019363:Cytochrome P-450 CYP1A1; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C022657:steroid hormone 6-beta-hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase