Persistent expression of 3-methylcholanthrene-inducible cytochromes P4501A in rat hepatic and extrahepatic tissues.
We reported earlier that 3-methylcholanthrene (MC) persistently induces hepatic ethoxyresorufin O-deethylase activities (CYP1A1) in rats for up to 45 days. In this investigation, we tested the hypotheses that persistent expression of CYP1A1 activities is paralleled by sustained induction of CYP1A1/CYP1A2 apoproteins and their mRNAs and that this phenomenon is mediated by mechanisms other than retention of MC in the rat. Rats were given MC (93 micromol/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 activities, apoprotein contents, and mRNA levels were sustained for several weeks after the last dose of MC treatment. MC also caused long-term induction of CYP1A1 in lungs and mammary glands. Rats treated with [(3)H]MC once daily for 4 days excreted 92. 3% of the administered radioactivity in feces and urine by day 15. The intrahepatic concentration of MC at the 15-day time point was 270 pmol/g. Dose-response studies showed that administration of MC (2 micromol/kg), which produced an intrahepatic concentration of 271 pmol/g after 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 MC in the body. Electrophoretic mobility shift assays revealed that persistent CYP1A1 induction by MC involved Ah receptor-independent mechanisms. In conclusion, 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.
Moorthy
B
B
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. bmoorthy@neo.bcm.tmc.edu
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008099:Liver / Q000201:enzymology*; D008748:Methylcholanthrene / Q000493:pharmacokinetics / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D020218:Response Elements
D002273:Carcinogens; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2