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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Phenacetin Deacetylase Activity in Human Liver Microsomes: Distribution, Kinetics, and Chemical Inhibition and Stimulation

Shoji Kudo, Ken Umehara, Masakiyo Hosokawa, Gohachiro Miyamoto, Kan Chiba and Tetsuo Satoh
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 80-88;
Shoji Kudo
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Ken Umehara
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Masakiyo Hosokawa
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Gohachiro Miyamoto
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Kan Chiba
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Tetsuo Satoh
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Abstract

Microsomal and cytosolic phenacetin deacetylase activities were examined in human liver and kidneys. Kinetic properties of the activities were also studied in human liver microsomes. Phenacetin deacetylase activity was predominantly localized in the liver microsomal fraction. The specific activities of phenacetin deacetylation in liver cytosol and in kidney microsomes and cytosol were all less than 5% of that in liver microsomes. In human liver microsomes, Eadie-Hofstee plots for phenacetin deacetylation were monophasic, indicating a single-enzyme catalytic reaction. The Michaelis-Menten parameters, Km andVmax, for the deacetylation were 4.7 mM and 5.54 nmol/min/mg of protein, respectively. The intrinsic clearance, calculated asVmax/Km, was 1.18 μl/min/mg of protein. Although the organophosphate bis(4-nitrophenyl)phosphoric acid markedly inhibited the reaction in human liver microsomes, the activity has a tolerance to the treatment of phenylmethylsulfonyl fluoride, a serine hydrolase inhibitor. Prazosin, a peripheral α1-adrenergic antagonist, noncompetitively inhibited the phenacetin deacetylation with aKi value of 19.0 μM. Flutamide, a nonsteroidal androgen receptor antagonist, stimulated the activity by up to 349%. This increase was accompanied by a decrease in theKm value and no change in theVmax value, resulting in an increase in the intrinsic clearance by up to 700% of the control. These results suggest that the phenacetin deacetylase localized in human liver microsomes has not only a catalytic site but also a negative and/or positive modulation site or sites.

Footnotes

  • Send reprint requests to: Dr. Shoji Kudo, Office of Pharmaceutical R & D Planning, Otsuka Pharmaceutical Co., Ltd., No. 2 Awajimachi Park Bldg. 5F, 2-6-6 Awajimachi, Chuo-ku, Osaka 541-0047, Japan. E-mail: kudos{at}ohq.otsuka.co.jp

  • Abbreviations:
    CYP
    cytochrome P450
    PMSF
    phenylmethylsulfonyl fluoride
    BNPP
    bis(4-nitrophenyl)phosphoric acid
    S-V
    substrate concentration-versus-initial-velocity
    • Received September 30, 1999.
    • Accepted March 16, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Phenacetin Deacetylase Activity in Human Liver Microsomes: Distribution, Kinetics, and Chemical Inhibition and Stimulation

Shoji Kudo, Ken Umehara, Masakiyo Hosokawa, Gohachiro Miyamoto, Kan Chiba and Tetsuo Satoh
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 80-88;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Phenacetin Deacetylase Activity in Human Liver Microsomes: Distribution, Kinetics, and Chemical Inhibition and Stimulation

Shoji Kudo, Ken Umehara, Masakiyo Hosokawa, Gohachiro Miyamoto, Kan Chiba and Tetsuo Satoh
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 80-88;
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