Profiling the hepatic effects of flutamide in rats: a microarray comparison with classical aryl hydrocarbon receptor ligands and atypical CYP1A inducers.
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 approximately 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 approximately 350 genes. Employing a gene-response compendium, FLU was compared with three classical aryl hydrocarbon receptor (AhR) ligands, 3-methylcholanthrene, benzo[a]pyrene, and beta-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.
Coe
Kevin J
KJ
Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.
Nelson
Sidney D
SD
Ulrich
Roger G
RG
He
Yudong
Y
Dai
Xudong
X
Cheng
Olivia
O
Caguyong
Michelle
M
Roberts
Chris J
CJ
Slatter
J Greg
JG
D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D016000:Cluster Analysis; D000090702:Constitutive Androstane Receptor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D005485:Flutamide / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods; D006984:Hypertrophy; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008748:Methylcholanthrene / Q000633:toxicity; D020411:Oligonucleotide Array Sequence Analysis; D009853:Omeprazole / Q000633:toxicity; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism
D000726:Androgen Antagonists; D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D008748:Methylcholanthrene; D005485:Flutamide; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole