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.

ABSTRACT

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.