Differential regulation of expression of hepatic and pulmonary cytochrome P4501A enzymes by 3-methylcholanthrene in mice lacking the CYP1A2 gene.
The cytochrome P4501A enzymes play important roles in carcinogen metabolism. We reported previously that 3-methylcholanthrene (MC) elicits a persistent induction of hepatic, pulmonary, and mammary microsomal cytochrome P450 (P450) 1A enzymes for several weeks after MC withdrawal. In this study, we tested the hypothesis that CYP1A2, a liver-specific P450 isozyme, plays an important role in the mechanisms governing persistent CYP1A1 induction by MC in liver but not in extra-hepatic tissues such as lung, which is devoid of endogenous CYP1A2. Administration of wild-type (WT) or CYP1A2-null mice with MC (100 micromol/kg i.p.) once daily for 4 days caused significant increases in hepatic CYP1A1/1A2 activities, apoprotein contents, and mRNA levels 1 day after carcinogen withdrawal compared with vehicle-treated controls. The induction persisted in the WT, but not CYP1A2-null animals, for up to 15 days. In the lung, MC caused persistent CYP1A1 induction for 15 days in both the genotypes. Since MC is almost completely eliminated by day 15, we hypothesize that CYP1A2 contributes to the up-regulation of CYP1A1 in liver, but not lung, by a novel mechanism, presumably involving a CYP1A2-dependent persistent metabolite. The studies demonstrate tissue-specific differences in the regulation of CYP1A by MC, a phenomenon that may have implications for human carcinogenesis caused by environmental chemicals.
Kondraganti
Sudha R
SR
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
Jiang
Weiwu
W
Moorthy
Bhagavatula
B
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis
D012333:RNA, Messenger; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2