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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of the Kinetics of β-Elimination Reactions of Selenocysteine Se-Conjugates in Human Renal Cytosol: Possible Implications for the Use as Kidney Selective Prodrugs

Martijn Rooseboom, Nico P. E. Vermeulen, Ioanna Andreadou and Jan N. M. Commandeur
Journal of Pharmacology and Experimental Therapeutics August 2000, 294 (2) 762-769;
Martijn Rooseboom
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Nico P. E. Vermeulen
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Ioanna Andreadou
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Jan N. M. Commandeur
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Abstract

This study was performed to evaluate whether selenocysteine Se-conjugates are substrates for human cysteine conjugate β-lyase enzymes. By testing kidney cytosols of three different humans, we studied interindividual differences in β-lyase enzymes in humans. A series of 22 selenocysteine Se-conjugates were tested in rat and human kidney cytosols to compare their ability to form selenol compounds by β-elimination. All compounds appeared to be good substrates for rat and human cysteine conjugate β-lyase enzymes. The β-lyase activity toward the selenocysteine Se-conjugates was comparable with those of the known nephrotoxic cysteine S-conjugateS-(2-chloro-1,1,2-trifluoroethyl)-l-cysteine in rats and humans. In rat kidney cytosol, between 22- and 877-fold higher β-elimination rates were observed compared with human kidney cytosol. Significant correlations (P < .0001) between three human kidney cytosols in β-lyase activities were found within the tested series of 22 compounds. Specific β-lyase activities and intrinsic clearances of β-elimination reactions ranged up to 3-fold, indicating that there are quantitative rather than qualitative interindividual differences in β-eliminating enzymes in humans. Furthermore, Se-alkyl selenocysteine conjugates showed a sterically dependent bioactivation to selenol compounds in humans but not in rats. The present study supports the hypothesis that selenocysteine Se-conjugates may be useful as prodrugs to target pharmacologically active selenol compounds (e.g., antitumor or chemoprotective) to the kidney in humans.

Footnotes

  • Send reprint requests to: Prof. Dr. Nico P. E. Vermeulen, Leiden/Amsterdam Center for Drug Research (LACDR), Division of Molecular Toxicology, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, the Netherlands. E-mail vermeule{at}chem.vu.nl

  • ↵1 Abraham and Cooper (1996) reported a mass of 45.8 kDa, whereas on recalculation of the mass from cDNA sequence, it appears to be 48.5 kDa, which was confirmed by Abraham (personal communication).

  • Abbreviations:
    Se-Cys
    selenocysteine Se
    CTFE-Cys
    S-(2-chloro-1,1,2-trifluoroethyl)-l-cysteine
    BTC
    S-(2-benzothiazolyl)-l-cysteine
    KMB
    α-keto-γ-methiolbutyric acid
    GS-MS
    gas chromatography-mass spectrometry
    • Received January 6, 2000.
    • Accepted April 19, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 2
1 Aug 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of the Kinetics of β-Elimination Reactions of Selenocysteine Se-Conjugates in Human Renal Cytosol: Possible Implications for the Use as Kidney Selective Prodrugs

Martijn Rooseboom, Nico P. E. Vermeulen, Ioanna Andreadou and Jan N. M. Commandeur
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 762-769;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of the Kinetics of β-Elimination Reactions of Selenocysteine Se-Conjugates in Human Renal Cytosol: Possible Implications for the Use as Kidney Selective Prodrugs

Martijn Rooseboom, Nico P. E. Vermeulen, Ioanna Andreadou and Jan N. M. Commandeur
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 762-769;
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