Abstract
The antiandrogen 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 3 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 with three classical aryl hydrocarbon receptor (AhR) ligands, 3-methylcholanthrene, benzo[a]pyrene, and β-naphthoflavone, and four atypical CYP1A inducers, indole-3-carbinol (I3C), omeprazole (OME), chlorpromazine (CPZ), and clotrimazole (CLO). The FLU gene response was comparable with 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 that was comparable with all the compounds except CPZ and CLO. FLU absorption, distribution, metabolism, and excretion (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.
Footnotes
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This work was supported by the University of Washington Fellowship and Rosetta Inpharmatics Summer Internship.
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Abstract presented at the 13th Annual Meeting of the North American International Society for the Study of Xenobiotics, Maui, Hawaii, October 23–27, 2005.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.009159.
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ABBREVIATIONS: FLU, flutamide; AhR, aryl hydrocarbon receptor; NQO, NAD(P)H:quinone oxidoreductase; TCDD, 2,3,7,8-tetrachloro-dibenzodioxin; PAH, polycyclic aromatic hydrocarbon(s); 3MC, 3-methylcholanthrene; BAP, benzo[a]pyrene; BNF, β-naphthoflavone; OME, omeprazole; CLO, clotrimazole; I3C, indole-3-carbinol; CPZ, chlorpromazine; ALT, alanine aminotransferase; ANOVA, analysis of variance; % LW/BW, percentage of liver weight to body weight ratio; ADME, absorption, distribution, metabolism, and excretion; Alas, aminolevulinic acid synthase; CAR, constitutive androstane receptor; PXR, pregnane X receptor.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
- Received December 29, 2005.
- Accepted March 29, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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