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TOXICOLOGY

Role of Cysteine S-Conjugate -Lyase in the Metabolism of Cisplatin

Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Cisplatin is nephrotoxic, but the mechanism by which cisplatin kills renal proximal tubule cells is not well defined. Inhibition of -glutamyl transpeptidase or pyridoxal 5'-phosphate (PLP)-dependent enzymes blocks the nephrotoxicity. Our hypothesis is that cisplatin is metabolized to a renal toxin through a platinum-glutathione conjugate to a reactive sulfur-containing compound. The final step in this bioactivation is the conversion of a platinum-cysteine S-conjugate to a reactive thiol by a PLP-dependent cysteine S-conjugate -lyase. LLC-PK₁ cells, a proximal tubule cell line with low cysteine S-conjugate -lyase activity, are used to study cisplatin nephrotoxicity. We proposed that the -elimination reaction catalyzed by cysteine S-conjugate -lyase is the rate-limiting step in the metabolism of cisplatin to a toxin in these cells. In this study, LLC-PK₁ cells were transfected with human glutamine transaminase K, which catalyzes the -elimination reaction. Cisplatin was significantly more toxic in confluent monolayers of cells with increased cysteine S-conjugate -lyase activity. In contrast, carboplatin, a non-nephrotoxic derivative of cisplatin, was 20-fold less toxic than cisplatin in confluent cells, and its toxicity was not altered by overexpression of cysteine S-conjugate -lyase. We propose that carboplatin is not nephrotoxic because it is not metabolized through this pathway. Dividing cells were more sensitive to both cisplatin and carboplatin toxicity. Overexpression of cysteine S-conjugate -lyase activity had no effect on the toxicity of either drug. These data demonstrate that cisplatin kills quiescent renal cells by a mechanism that is distinct from the mechanism by which it kills dividing cells and that the renal toxicity of cisplatin is dependent on cysteine S-conjugate -lyase activity.

Address correspondence to: Dr. Marie H. Hanigan, Biomedical Research Center Room 264, 975 N.E. 10th St., Oklahoma City, Oklahoma. E-mail: marie-hanigan{at}ouhsc.edu

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