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Drug Metabolism and Disposition Fast Forward
First published on April 12, 2006; DOI: 10.1124/dmd.105.009159

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Received for publication December 29, 2005.
Revised March 28, 2006.
Accepted for publication March 29, 2006.

Profiling the Hepatic Effects of Flutamide in Rats: A Microarray Comparison with Classical AhR Ligands and Atypical CYP1A Inducers

Kevin J Coe 1, Sidney D Nelson 1, Roger G Ulrich 2, Yudong D He 2, Xudong Dai 2, Olivia Cheng 2, Michelle Caguyong 2, Chris J Roberts 2, J Greg Slatter 3*

1 Department of Medicinal Chemistry, University of Washington, Seattle, Washington 2 Rosetta Inpharmatics LLC (A wholly owned subsidiary of Merck & Co., Inc.) Seattle, Washington 3 Rosetta Impharmatics (A subsidiary of Merck & Co.)

* Address correspondence to: E-mail: greg_slatter{at}merck.com

Abstract

The anti-androgen flutamide (FLU) is used primarily for prostate cancer and is an idiosyncratic hepatotoxicant that sometimes causes severe liver problems. To investigate FLU's overt hepatic effects, especially on inducible drug clearance-related gene networks, FLU's hepatic gene expression profile was examined in female Sprague-Dawley rats using ~22,500 oligonucleotide microarrays. Rats were dosed daily for three days with FLU at 500, 250, 62.5, 31.3, and 15.6 mg/kg/day, and hepatic RNA was isolated. FLU resulted in the dose dependent regulation of ~350 genes. Employing a gene response compendium, FLU was compared to three classical aryl hydrocarbon receptor (AhR) ligands, 3-methylcholanthrene (3MC), benzo[a]pyrene (BAP), and beta-naphthoflavone (BNF), and four atypical CYP1A inducers, indole-3-carbinol (I3C), omeprazole (OME), chlorpromazine (CPZ), and clotrimazole (CLO). The FLU gene response was comparable to classical AhR ligands across a signature AhR ligand gene set that included CYP1A1 and other members of the AhR gene battery. Dose-related responses of CYP1 genes established a maximum response ceiling and discerned potency differences in atypical inducers. FLU had a sharp down-regulation of c-fos which was comparable to all compounds except CPZ and CLO. FLU ADME gene expression analysis revealed that FLU as well as I3C and OME induced CYP2B and CYP3A, distinguishing them from the classical AhR ligands. By using a compendium of gene expression profiles, FLU was shown to signal in rats similar to an AhR activator with additional CYP2B and CYP3A effects that most resembled the ADME gene expression pattern of the atypical CYP1A inducers I3C and OME.


Key words: Ah receptor, bioactivation, chemical toxicology, cytochrome P450, drug discovery, drug-induced hepatotoxicity, idiosyncratic drug reactions, induction, microarrays


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