Differential Regulation of Expression of Hepatic and Pulmonary Cytochrome P4501A Enzymes by 3-Methylcholanthrene in Mice Lacking theCYP1A2 Gene
- Dr. Bhagavatula Moorthy, Associate Professor of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail: bmoorthy{at}bcm.tmc.edu
Abstract
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 μmol/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.
Footnotes
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This work was supported in part by U.S. Public Health Service Grant R01 ES09132 from the National Institute of Environmental Health Sciences to B.M.
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DOI: 10.1124/jpet.102.039982
- Abbreviations:
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- MC
- 3-methylcholanthrene
- PAH
- polycyclic aromatic hydrocarbons
- P450
- cytochrome P450
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- AHR
- Ah receptor
- AHRE
- Ah response elements
- HRP
- horseradish peroxidase
- WT
- wild-type
- CO
- corn oil
- EROD
- ethoxyresorufin O-deethylase
- MROD
- methoxyresorufin O-demethylase
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- Received June 6, 2002.
- Accepted August 9, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
