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ToxSci Advance Access originally published online on April 15, 2003
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Toxicological Sciences 73, 108-113 (2003)
Copyright © 2003 by the Society of Toxicology

MOLECULAR AND GENETIC TOXICOLOGY

Cytochrome P4501A1 and 1A2 Gene Expression in the Liver of 3-Methylcholanthrene- and o-Aminoazotoluene-Treated Mice: A Comparison between PAH-Responsive and PAH-Nonresponsive Strains

Ludmila Yu. Zacharova*, Ludmila F. Gulyaeva*, Vyacheslav V. Lyakhovich*, Olga N. Mikhailova*,{dagger},1, Olga A. Timofeeva{dagger}, Maxim L. Filipenko{dagger} and Vasily I. Kaledin{ddagger}

* Institute of Molecular Biology and Biophysics, Novosibirsk 630127, Russia; {dagger} Institute of Bioorganic Chemistry, Novosibirsk 630090, Russia; and {ddagger} Institute of Cytology and Genetics, Novosibirsk 630090, Russia

The objective of this study was to investigate cytochrome P4501A1 and 1A2 mRNA, protein, and enzyme activity in the liver of male mice differing in the aryl hydrocarbon receptor (AhR) genotype during treatment with the carcinogenic compounds 3-methylcholanthrene (MC) and o-aminoazotoluene (OAT). The basal levels of the CYP1A1 and CYP1A2 enzyme activities were comparable among the mouse strains examined. Significant interstrain variations were observed after treatment by the inducers: EROD and MROD activities were considerably increased in C57BL and A/Sn mice, but not in AKR, SWR, and DBA mice. Western blot analysis did not detect CYP1A1 in the liver of untreated mice. Treatment of mice with MC or OAT caused CYP1A1 accumulation in the liver of C57BL and A/Sn mice, but not in AKR, SWR, and DBA mice. CYP1A2 was detected in all studied mouse strains in both untreated and inducer-treated livers. The results of multiplex RT-PCR showed that the CYP1A1 mRNA in the liver of untreated mice was hardly detectable while constitutive expression of the CYP1A2 gene was rather high. After treatment with MC and OAT the CYP1A1 mRNA level dramatically increased in all strains examined while the increase in the CYP1A2 mRNA level was not striking. This finding did not correlate with the data on the enzyme activity. Our results demonstrated a discrepancy between the transcription of CYP1A1 and CYP1A2 genes and the inducibility of these enzymes in the liver of mice, suggesting a posttranscriptional mechanism of cytochrome P4501A regulation. This comparison between aromatic hydrocarbon-responsive and -nonresponsive strains could contribute to understanding of cytochrome P4501A gene regulation in the liver under the influence of environmental factors.

Key Words: liver; inbred mouse strains; cytochrome P4501A1 and 1A2; aryl hydrocarbon receptor; 3-methylcholanthrene; o-aminoazotoluene.


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