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Research ArticleArticle

Porcine Kidney Microsomal Cysteine S-ConjugateN-Acetyltransferase-CatalyzedN-Acetylation of Haloalkene-Derived CysteineS-Conjugates

Torsten Kraus, Viuita Uttamsingh, M.W. Anders and Sabine Wolf
Drug Metabolism and Disposition April 2000, 28 (4) 440-445;
Torsten Kraus
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Viuita Uttamsingh
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M.W. Anders
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Sabine Wolf
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Abstract

N-Acetylation of xenobiotic-derived cysteineS-conjugates is a key step in the mercapturic acid pathway. The aim of this study was to investigate theN-acetylation of haloalkene-derivedS-haloalkyl and S-haloalkenyl cysteineS-conjugates by porcine kidney cysteineS-conjugate N-acetyltransferase (NAcT). A radioactive assay for the quantification of NAcT activity was developed as a new method for partial purification of the enzyme, which was necessitated by the substantial loss of activity during the immunoaffinity chromatography method. 3-[(3-Cholamidopropyl)dimethylammonio]-1-propane-sulfonate, rather thanN,N-bis[3-gluconamidopropyl]deoxycholamide, was used to solubilize the NAcT from porcine kidney microsomes in the revised procedure. The partially purified NAcT was free of detectable aminoacylase activity. Although low acetyl-coenzyme A hydrolase activity was observed, its effect on the assay was minimized by addition of excess acetyl-coenzyme A in the NAcT assay mixture. Attempts to separate the residual hydrolase activity from NAcT by different chromatographic procedures were either unsuccessful or lead to inactivation of NAcT. Most of the cysteineS-conjugates studied were N-acetylated by NAcT. Although the apparent Km values for the cysteine S-conjugates studied differed by a factor of ∼2.5 (124–302 μM), a greater than 15-fold difference in the apparent Vmax (0.75–15.6 nmol/h) andVmax/Km(0.008–0.126 × 10−3 l h−1) values was observed. These data show that a range of haloalkene-derived cysteineS-conjugates serve as substrates for pig kidney NAcT. The significant differences in cytotoxicity of these conjugates may be a result of more variable deacetylation rates of the corresponding mercapturates.

Footnotes

  • Send reprint requests to: Sabine Wolf, Institut für Biochemie, Technische Universität Darmstadt, Petersenstr. 22, 64287 Darmstadt, Germany. E-mail:swolf{at}pop.tu-darmstadt.de

  • This research was supported in part by National Institutes of Environmental Health Sciences Grant ES-03127 to M.W.A. and by the Deutsche Forschungsgemeinschaft (Grant Wo 569/1-1) to S.W.

  • Abbreviations used are::
    NAcT
    cysteineS-conjugate N-acetyltransferase
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]-1-propane-sulfonate
    PEG
    polyethylene glycol
    cmc
    critical micellar concentration
    CoA
    coenzyme A
    TLC
    thin-layer chromatography
    • Received August 17, 1999.
    • Accepted December 22, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (4)
Drug Metabolism and Disposition
Vol. 28, Issue 4
1 Apr 2000
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Research ArticleArticle

Porcine Kidney Microsomal Cysteine S-ConjugateN-Acetyltransferase-CatalyzedN-Acetylation of Haloalkene-Derived CysteineS-Conjugates

Torsten Kraus, Viuita Uttamsingh, M.W. Anders and Sabine Wolf
Drug Metabolism and Disposition April 1, 2000, 28 (4) 440-445;

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Research ArticleArticle

Porcine Kidney Microsomal Cysteine S-ConjugateN-Acetyltransferase-CatalyzedN-Acetylation of Haloalkene-Derived CysteineS-Conjugates

Torsten Kraus, Viuita Uttamsingh, M.W. Anders and Sabine Wolf
Drug Metabolism and Disposition April 1, 2000, 28 (4) 440-445;
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