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ToxSci Advance Access published online on April 18, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm089
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Microsomal Expoxide Hydrolase is Required for 7,12–Dimethylbenz[a]anthracene (DMBA) Induced Immunotoxicity in Mice

Jun Gao, Fredine T. Lauer, Leah A. Mitchell and Scott W. Burchiela

The University of New Mexico College of Pharmacy Toxicology Program Albuquerque, NM 87131-0001

a Corresponding author: 1 University of New Mexico - MSC09 5360, Albuquerque, NM 87131-0001, sburchiel{at}salud.unm.edu, 505-272-0920, 505-272-6749 (FAX)

Received April 3, 2007; revision received April 3, 2007; accepted April 6, 2007


  Abstract

Microsomal epoxide hydrolase (mEH, EPHX1) is involved in the metabolism of chemicals to generate dihydrodiol intermediates in presence of the cytochrome P450. We have previously shown that 7,12-dimethylbenz[a]anthracene (DMBA) can suppress both cell-mediated and humoral immune response in wild-type (WT) C57BL/6N mice but not in CYP 1B1 null mice. In the present studies, we hypothesized the critical metabolite responsible for DMBA induced immunotoxicity is likely to be the 3,4-dihydrodiol-1,2-epoxide metabolite of DMBA, which requires mEH for formation. Mice were gavaged orally with DMBA (0, 17, 50 and 150 mg/kg) once a day for 5 days. Immune function and other assays were performed on day 7. Our data showed that unlike WT mice, DMBA treatment of mEH null mice produced no alterations in the body weight, spleen weight or spleen cellularity. Similarly, DMBA treatments did not affect the PFC response in mEH null mice. NK activity was not altered by DMBA treatment in mEH null mice. T-cell mitogenesis was partially suppressed by 50 and 150 mg/kg DMBA treatments of mEH null mice, but B cell mitogenesis was not affected. Finally, we assessed the biodistribution of DMBA in both C57BL/6N WT and mEH null mice in spleen, thymus and liver after 24 hr and 7 days oral gavage. The concentrations of DMBA in each organ were not significantly different in WT and in mEH null mice. Collectively, these results demonstrate that mEH (EPHX1 gene) is a crucial enzyme for metabolic activation of DMBA in vivo leading to immunosuppression of spleen cells.


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Home page
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J. Gao, L. A. Mitchell, F. T. Lauer, and S. W. Burchiel
p53 and ATM/ATR Regulate 7,12-Dimethylbenz[a]anthracene-Induced Immunosuppression
Mol. Pharmacol., January 1, 2008; 73(1): 137 - 146.
[Abstract] [Full Text] [PDF]


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