ToxSci Advance Access originally published online on June 12, 2009
Toxicological Sciences 2009 111(1):19-26; doi:10.1093/toxsci/kfp130
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Octachlorostyrene Induces Cytochrome P450, UDP-glucuronosyltransferase, and Sulfotransferase via the Aryl Hydrocarbon Receptor and Constitutive Androstane Receptor
* Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland
1 To whom correspondence should be addressed at Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550 Japan. Fax: +81-52-744-2126. E-mail: tnasu23{at}med.nagoya-u.ac.jp.
Received March 12, 2009; accepted June 1, 2009
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Abstract |
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Octachlorostyrene (OCS) is a byproduct produced in the process of synthesis of chlorinated compounds. There are some reports concerning environmental contamination by OCS, but few on the toxicological effects on human. Drug-metabolizing enzymes may play an important role in toxicity through metabolic activation or deactivation of OCS. In this study, we investigated whether OCS influences these enzymes using wild-type and aryl hydrocarbon receptor (Ahr)-null mice; AhR regulates cytochrome P450 (CYP) 1A, UDP-glucuronosyltransferase (UGT), or sulfotransferase (SULT). Both mouse lines were treated with OCS (0, 32, and 64 µmol/kg) for 4 days by gavage. As a reference, the mice were treated with 20 mg/kg 3-methylcholanthrene (3MC) for 4 days. OCS treatment increased the expression of CYP 1A1 and CYP1A2 mRNA and ethoxyresorfin O-deethylase activity only in the wild-type mice, similar to that of the AhR activator 3MC. OCS treatment increased expression of UGT1A6 and SULT 1A1 mRNA and their associated enzyme activities only in Ahr-null mice, whereas 3MC still influenced these enzymes only in wild-type mice. OCS induced constitutive androstane receptor (CAR) only in Ahr-null mice, and the target gene CYP2B10 mRNA was induced more strongly in Ahr-null mice than in wild-type mice. 3MC slightly induced CYP2B10 mRNA only in the wild-type mice. These results suggest that CAR is involved in regulation of the UGT and SULT genes by OCS. Thus, OCS may regulate CYP1A via AhR, whereas it controls UGT1A6 and SULT1A via CAR.
Key Words: aryl hydrocarbon receptor; constitutive androstendione receptor; octachlorostyrene.