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Research ArticleArticle

Role of Enzymatic N-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity

Masato Ohbuchi, Masaaki Miyata, Daichi Nagai, Miki Shimada, Kouichi Yoshinari and Yasushi Yamazoe
Drug Metabolism and Disposition January 2009, 37 (1) 97-105; DOI: https://doi.org/10.1124/dmd.108.021964
Masato Ohbuchi
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Masaaki Miyata
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Daichi Nagai
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Miki Shimada
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Kouichi Yoshinari
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Yasushi Yamazoe
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Abstract

Flutamide is used for prostate cancer therapy but occasionally induces severe liver injury. Flutamide is hydrolyzed in the body into 5-amino-2-nitrobenzotrifluoride (FLU-1) and then further oxidized. In our previous study, N-hydroxy FLU-1 (FLU-1 N-OH) was detected in the urine of patients and exhibited cytotoxicity in rat primary hepatocytes. In the present study, we have assessed the roles of FLU-1 N-oxidation and hepatic glutathione (GSH) depletion in liver injury. FLU-1 (200 mg/kg p.o.) was administered to C57BL/6 mice for 5 days together with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) (3 mg/kg i.p.) for the first 3 days. Mice were fasted for the last 2 days to deplete hepatic GSH. Administration of FLU-1 alone did not affect serum alanine aminotransferase activities (ALT), whereas coadministration of FLU-1 and TCPOBOP significantly increased ALT in fasted mice but not in nonfasted mice. Microsomal FLU-1 N-hydroxylation was enhanced approximately 5 times by TCPOBOP treatment. Flutamide metabolite-protein adducts were detected in liver microsomes incubated with FLU-1 N-OH, but not with FLU-1 and flutamide, by immunoblotting using antiflutamide antiserum. In the presence of mouse liver cytosol, FLU-1 N-OH was reduced back into FLU-1. This enzymatic reduction required NAD(P)H as a cofactor. The reduction was enhanced by the coexistence of NAD(P)H and GSH, whereas it was markedly inhibited by allopurinol (20 μM). By using purified bovine xanthine oxidase, the reduction was observed in the presence of NAD(P)H. These results suggest that FLU-1 N-OH is involved in flutamide-induced hepatotoxicity and that cytosolic reduction of FLU-1 N-OH plays a major role in protection against flutamide-induced hepatotoxicity.

Footnotes

  • This study was supported by a grant-in-aid from the Ministry of Education, Science, and Culture, Japan [Grants 17390039 and 17590114]; and a grant-in-aid from the Ministry of Health, Labor, and Welfare, Japan [Grant H17-toxico-ippan-001].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.021964.

  • ABBREVIATIONS: FLU-1, 5-amino-2-nitrobenzotrifluoride; FLU-3, 5-amino-2-nitro-4-hydroxybenzotrifluoride; FLU-1 N-OH, N-hydroxy-5-amino-2-nitrobenzotrifluoride; P450, cytochrome P450; GSH, glutathione; GST, glutathione S-transferase; GSSG, glutathione (oxidized form); CDNB, 1-chloro-2,4-dinitrobenzene; TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene; β-NF, β-naphthoflavone; PCN, pregnenolone-16α-carbonitrile; BSA, bovine serum albumin; ALT, alanine aminotransferase; HPLC, high-performance liquid chromatography; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; KLH, keyhole limpet hemocyanin.

    • Received April 21, 2008.
    • Accepted September 29, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (1)
Drug Metabolism and Disposition
Vol. 37, Issue 1
1 Jan 2009
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Research ArticleArticle

Role of Enzymatic N-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity

Masato Ohbuchi, Masaaki Miyata, Daichi Nagai, Miki Shimada, Kouichi Yoshinari and Yasushi Yamazoe
Drug Metabolism and Disposition January 1, 2009, 37 (1) 97-105; DOI: https://doi.org/10.1124/dmd.108.021964

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Research ArticleArticle

Role of Enzymatic N-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity

Masato Ohbuchi, Masaaki Miyata, Daichi Nagai, Miki Shimada, Kouichi Yoshinari and Yasushi Yamazoe
Drug Metabolism and Disposition January 1, 2009, 37 (1) 97-105; DOI: https://doi.org/10.1124/dmd.108.021964
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