Abstract
The effects of phenobarbital treatment on the expression of the cytochrome P-450 (CYP or P-450) enzyme CYP1A2 in the livers of mice of various strains were examined. Phenobarbital induced the expression of CYP1A2 at the levels of mRNA, protein, and enzyme activity (methoxyresorufin O-demethylation and metabolic activation of 2-amino-3-methylimidazo[4,5-f]quinoline) in both aryl hydrocarbon-responsive [C57BL/6NCrj (C57BL/6), C3H/HeJSlc] and -nonresponsive (DBA/2NCrj, AKR/JSea, NZB/NSlc) mouse strains. The induction of CYP2B10, which is known as a phenobarbital-inducible P-450 in mice, was prominent in the livers of all five strains examined, whereas clear inductive effects on the P-450 CYP2B9 were not observed in female C57BL/6 and female DBA/2NCrj mice. These results indicate that CYP1A2 is a member of the family of phenobarbital-inducible genes in mice and suggest that the aryl hydrocarbon receptor-dependent induction pathway is not involved in the induction of CYP1A2. This concept is in accordance with those proposed by other laboratories recently using the AhR knockout mice. The following are new observations of this report. The magnitude of the increases in the CYP1A2 mRNA, protein, and enzyme activities were comparable among these three levels (ranging from 1.4- to 3.1-fold), suggesting that the induction of CYP1A2 by phenobarbital is mainly determined at a pretranslational level. Cyclobarbital, pentobarbital, and secobarbital also induced CYP1A2 mRNA in primary culture hepatocytes from C57BL/6 mice. Barbital, in contrast, did not show any clear inductive effect on CYP1A2 mRNA.
Footnotes
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Send reprint requests to: Tsutomu Sakuma, Ph.D., Department of Toxicology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930–01, Japan. E-mail: tsakuma{at}ms.toyamampu.ac.jp
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This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Culture, Sports, and Science of Japan, and by the Smoking Research Foundation.
- Abbreviations used are::
- CYP
- cytochrome P-450 (for individual form)
- AhR
- aryl hydrocarbon receptor
- AKR
- AKR/JSea
- C3H
- C3H/HeJSlc
- C57BL/6
- C57BL/6Ncrj
- DBA/2
- DBA/2NCrj
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- IQ
- 2-amino-3-methylimidazo[4,5-f]quinoline
- 3-methylcholanthrene (3-MC)
- MROD
- methoxyresorufin-O-demethylase
- NZB, NZB/NSlc
- P-450
- cytochrome P-450
- PCR
- polymerase chain reaction
- PROD
- propoxyresorufin-O-dealkylase
- S. typhimurium
- Salmonella typhimurium
- Received June 2, 1998.
- Accepted November 16, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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