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
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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
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↵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