Persistent expression of 3-methylcholanthrene-inducible cytochromes P4501Ain rat hepatic and extrahepatic tissues

We reported earlier that 3-methylcholanthrene (MC) persistently induces hep atic ethoxyresorufin O-deethylase activities (CYP1A1) in rats for up to 45 days. In this investigation, we tested the hypotheses that persistent expre ssion of CYP1A1 activities is paralleled by sustained induction of CYP1A1/C YP1A2 apoproteins and their mRNAs and that this phenomenon is mediated by m echanisms other than retention of MC in the rat. Rats were given MC (93 mmo l/kg) i.p., once daily for 4 days, and CYP1A1/1A2 parameters were measured in liver at selected time points. MC-elicited increases in CYP1A1/1A2 activ ities, apoprotein contents, and mRNA levels were sustained for several week s after the last dose of MC treatment. MC also caused long-term induction o f CYP1A1 in lungs and mammary glands. Rats treated with [H-3]MC once daily for 4 days excreted 92.3% of the administered radioactivity in feces and ur ine by day 15. The intrahepatic concentration of MC at the 15-day time poin t was 270 pmol/g. Dose-response studies showed that administration of MC (2 mu mol/kg), which produced an intrahepatic concentration of 271 pmol/g aft er 24 h, did not induce CYP1A1/1A2 activities, strongly suggesting that the sustained induction of CYP1A1/1A2 was not due to retention of the parent M C in the body. Electrophoretic mobility shift assays revealed that persiste nt CYP1A1 induction by MC involved Ah receptor-independent mechanisms. In c onclusion, our results support the hypothesis that persistent expression of CYP1A1/1A2 by MC is mediated by mechanisms independent of the retention of the parent carcinogen.