Fig. 2.

Bioactivation of cisplatin to a nephrotoxin. The first step of cisplatin metabolism is the formation of a GSH-conjugate catalyzed by GST. As the cisplatin-GSH-conjugate passes through the kidney, it is cleaved by GGT to a cysteinyl-glycine-conjugate, which is further converted to a cysteine-conjugate by APN. GGT and APN are both plasma membrane-bound enzymes with the catalytic domain exposed to the extracellular surface. As the cisplatin-cysteine-conjugate enters the proximal tubular epithelial cell, it is further metabolized by a pyridoxal 5′-phosphate-dependent enzyme, CCBL, to a highly reactive and nephrotoxic thiol that would bind to proteins. The cytosolic glutamine transaminase K and especially the mitochondrial aspartate aminotransferase are the major CCBLs involved in the bioactiviation of cisplatin-cysteine-conjugate. GST, glutathione transferase; GGT, gamma glutamyl transpeptidase; APN, aminopeptidase N; CCBL, cysteine-S-conjugate beta-lyase.