%0 Journal Article %A Lei Zhang %A Marie H. Hanigan %T Role of Cysteine S-Conjugate β-Lyase in the Metabolism of Cisplatin %D 2003 %R 10.1124/jpet.103.052225 %J Journal of Pharmacology and Experimental Therapeutics %P 988-994 %V 306 %N 3 %X Cisplatin is nephrotoxic, but the mechanism by which cisplatin kills renal proximal tubule cells is not well defined. Inhibition of γ-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 β-lyase. LLC-PK1 cells, a proximal tubule cell line with low cysteine S-conjugate β-lyase activity, are used to study cisplatin nephrotoxicity. We proposed that the β-elimination reaction catalyzed by cysteine S-conjugate β-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 β-elimination reaction. Cisplatin was significantly more toxic in confluent monolayers of cells with increased cysteine S-conjugate β-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 β-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 β-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 β-lyase activity. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/306/3/988.full.pdf