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ToxSci Advance Access published online on January 17, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn007
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Persistent Induction of Hepatic and Pulmonary Phase II Enzymes by 3-Methylcholanthrene in Rats

Sudha R. Kondraganti*, Weiwu Jiang*, Anil K. Jaiswal{dagger} and Bhagavatula Moorthy*,1

* Department of Pediatrics, Baylor College of Medicine, Houston, TX {dagger} Department of Pharmacology, The University of Maryland School of Medicine, Baltimore, MD

1 Corresponding Author: Bhagavatula Moorthy, Ph.D. Associate Professor of Pediatrics, Baylor College of Medicine, 6621 Fannin, FC 530.01, Houston, TX 77030, Email: bmoorthy{at}bcm.tmc.edu. Tel: [832] 824-3266, FAX: [832] 825-3204

Received October 28, 2007; revision received January 6, 2008; accepted January 7, 2008


  Abstract

We reported earlier that exposure of rats to 3-methylcholanthrene [MC] causes sustained induction of hepatic cytochrome P450 (CYP)1A expression for up to 45 days by mechanisms other than persistence of the parent MC (Moorthy, J. Pharmacology. Exp. There., 294, 313-322, 2000). The CYP1A genes are members of the Ah gene battery that also encode CYP1B1 and phase II enzymes such as glutathione S-transferase (GST-{alpha}), UDP glucuronyl tranferase (UGT)1A, NAD[P]H: quinone oxidoreductase I [NQO1], aldehyde dehydrogenase (ALDH), etc. Therefore, in this investigation, we tested the hypothesis that MC elicits persistent induction of CYP1B1 and phase II genes, which are in part regulated by the Ah receptor [AHR]. Female Sprague-Dawley rats were treated with MC [100 µmol/kg], i.p., once daily for 4 days, and expression of CYP1B1 and several phase II [e.g., glutathione-S-transferase [GST]-{alpha}, NAD[P]H: quinone oxidoreductase I [NQO1] genes and their corresponding proteins were determined in lung and liver. The major finding was that MC persistently induced [3-10 fold] the expression of several phase II enzymes, including GST-{alpha}, NQO1, UGT1A1, ALDH, and epoxide hydrolase (EPHX) in both tissues for up to 28 days. However, MC did not elicit sustained induction of CYP1B1. Our results thus support the hypothesis that MC elicits coordinated and sustained induction of phase II genes presumably via persistent activation of the AHR, a phenomenon that may have implications for chemical-induced carcinogenesis and chemopreventive strategies in humans.

Key Words: 3-methylcholanthrene; phase II enzymes; CYP1A1; gene expression; carcinogenesis; CYP1B1; Ah receptor; NAD[P]H: quinone oxidoreductase; rat; in vivo.


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