Vol. 294, Issue 2, 762-769, August 2000

Evaluation of the Kinetics of -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

Leiden/Amsterdam Center for Drug Research, Division of Molecular Toxicology, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

This study was performed to evaluate whether selenocysteine Se-conjugates are substrates for human cysteine conjugate -lyase enzymes. By testing kidney cytosols of three different humans, we studied interindividual differences in -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 -elimination. All compounds appeared to be good substrates for rat and human cysteine conjugate -lyase enzymes. The -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 -elimination rates were observed compared with human kidney cytosol. Significant correlations (P < .0001) between three human kidney cytosols in -lyase activities were found within the tested series of 22 compounds. Specific -lyase activities and intrinsic clearances of -elimination reactions ranged up to 3-fold, indicating that there are quantitative rather than qualitative interindividual differences in -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.