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Research ArticleArticle

Human Arylacetamide Deacetylase Is a Principal Enzyme in Flutamide Hydrolysis

Akinobu Watanabe, Tatsuki Fukami, Miki Nakajima, Masataka Takamiya, Yasuhiro Aoki and Tsuyoshi Yokoi
Drug Metabolism and Disposition July 2009, 37 (7) 1513-1520; DOI: https://doi.org/10.1124/dmd.109.026567
Akinobu Watanabe
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Tatsuki Fukami
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Miki Nakajima
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Masataka Takamiya
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Yasuhiro Aoki
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Tsuyoshi Yokoi
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This article has a correction. Please see:

  • Correction to “Human Arylacetamide Deacetylase Is a Principal Enzyme in Flutamide Hydrolysis” - June 01, 2014

Abstract

Flutamide, an antiandrogen drug, is widely used for the treatment of prostate cancer. The initial metabolic pathways of flutamide are hydroxylation and hydrolysis. It was recently reported that the hydrolyzed product, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1), is further metabolized to N-hydroxy FLU-1, an assumed hepatotoxicant. However, the esterase responsible for the flutamide hydrolysis has not been characterized. In the present study, we found that human arylacetamide deacetylase (AADAC) efficiently hydrolyzed flutamide using recombinant AADAC expressed in COS7 cells. In contrast, carboxylesterase1 (CES1) and CES2, which are responsible for the hydrolysis of many drugs, could not hydrolyze flutamide. AADAC is specifically expressed in the endoplasmic reticulum. Flutamide hydrolase activity was highly detected in human liver microsomes (Km, 794 ± 83 μM; Vmax, 1.1 ± 0.0 nmol/min/mg protein), whereas the activity was extremely low in human liver cytosol. The flutamide hydrolase activity in human liver microsomes was strongly inhibited by bis-(nonylphenyl)-phenylphosphate, diisopropylphosphorofluoride, and physostigmine sulfate (eserine) but moderately inhibited by sodium fluoride, phenylmethylsulfonyl fluoride, and disulfiram. The same inhibition pattern was obtained with the recombinant AADAC. Moreover, human liver and jejunum microsomes showing AADAC expression could hydrolyze flutamide, but human pulmonary and renal microsomes, which do not express AADAC, showed slight activity. In human liver microsomal samples (n = 50), the flutamide hydrolase activities were significantly correlated with the expression levels of AADAC protein (r = 0.66, p < 0.001). In conclusion, these results clearly showed that flutamide is exclusively hydrolyzed by AADAC. AADAC would be an important enzyme responsible for flutamide-induced hepatotoxicity.

Footnotes

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

  • doi:10.1124/dmd.109.026567.

  • ABBREVIATIONS: FLU-1, 4-nitro-3-(trifluoromethyl)phenylamine; CES, carboxylesterase; HLM, human liver microsome; BNPP, bis-(nonylphenyl)-phenylphosphate; AADAC, arylacetamide deacetylase; DFP, diisopropylphosphorofluoride; eserine, physostigmine sulfate; PMSF, phenylmethylsulfonyl fluoride; AgNO3, silver nitrate; CdCl2, cadmium chloride; CoCl2, cobaltous chloride; CuCl2, cupric chloride; PNPA, p-nitrophenyl acetate; NaF, sodium fluoride; HLC, human liver cytosol; HJM, human jejunum microsome; HPM, human pulmonary microsome; HRM, human renal microsome; RT-PCR, reverse transcription-polymerase chain reaction; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; SNP, single nucleotide polymorphism; DMSO, dimethyl sulfoxide; HPLC, high-performance liquid chromatography.

    • Accepted March 26, 2009.
    • Received January 19, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (7)
Drug Metabolism and Disposition
Vol. 37, Issue 7
1 Jul 2009
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Research ArticleArticle

Human Arylacetamide Deacetylase Is a Principal Enzyme in Flutamide Hydrolysis

Akinobu Watanabe, Tatsuki Fukami, Miki Nakajima, Masataka Takamiya, Yasuhiro Aoki and Tsuyoshi Yokoi
Drug Metabolism and Disposition July 1, 2009, 37 (7) 1513-1520; DOI: https://doi.org/10.1124/dmd.109.026567

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Research ArticleArticle

Human Arylacetamide Deacetylase Is a Principal Enzyme in Flutamide Hydrolysis

Akinobu Watanabe, Tatsuki Fukami, Miki Nakajima, Masataka Takamiya, Yasuhiro Aoki and Tsuyoshi Yokoi
Drug Metabolism and Disposition July 1, 2009, 37 (7) 1513-1520; DOI: https://doi.org/10.1124/dmd.109.026567
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