Evaluation of the kinetics of beta-elimination reactions of selenocysteine Se-conjugates in human renal cytosol: possible implications for the use as kidney selective prodrugs.
This study was performed to evaluate whether selenocysteine Se-conjugates are substrates for human cysteine conjugate beta-lyase enzymes. By testing kidney cytosols of three different humans, we studied interindividual differences in beta-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 beta-elimination. All compounds appeared to be good substrates for rat and human cysteine conjugate beta-lyase enzymes. The beta-lyase activity toward the selenocysteine Se-conjugates was comparable with those of the known nephrotoxic cysteine S-conjugate S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine in rats and humans. In rat kidney cytosol, between 22- and 877-fold higher beta-elimination rates were observed compared with human kidney cytosol. Significant correlations (P <.0001) between three human kidney cytosols in beta-lyase activities were found within the tested series of 22 compounds. Specific beta-lyase activities and intrinsic clearances of beta-elimination reactions ranged up to 3-fold, indicating that there are quantitative rather than qualitative interindividual differences in beta-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.
Rooseboom
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M
Leiden/Amsterdam Center for Drug Research, Division of Molecular Toxicology, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, The Netherlands.
Vermeulen
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Andreadou
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Commandeur
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D000368:Aged; D000818:Animals; D003600:Cytosol / Q000201:enzymology; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D008190:Lyases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D017279:Selenocysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D011355:Prodrugs; D017279:Selenocysteine; D008190:Lyases; C034278:selenocysteine lyase