title: Possible role of cysteine-S-conjugate β-lyase in species differences in cisplatin nephrotoxicity.
abstract: To better understand species differences in cisplatin nephrotoxicity, we focused on renal cysteine-S-conjugate β-lyase (C-S lyase), which may play a crucial role in the metabolism of platinum (Pt)-cysteine conjugates. Aminooxyacetic acid hemihydrochloride (AOAA), an inhibitor of C-S lyase, reduced renal injuries due to cisplatin in rats, suggesting involvement of C-S lyase. On day 5 following a bolus cisplatin injection, three species showed in vivo nephrotoxic potentials in the order of rats>mice=rabbits (the highest to lowest), based on body surface. The levels of renal Pt residue at the nephrotoxic dose were in order of rabbits>rats>mice. Meanwhile, the activity of endogenous (basal) mitochondrial aspartate aminotransferase (AST), one of the C-S lyases, in the renal cortex of naive animals was rats>mice=rabbits. In a qualitative Western blot analysis, expression of mitochondrial C-S lyase in the kidney was observed at approximately 37kDa in all five species used. In in vitro studies, the cytotoxicity of cisplatin was dependent on the expression level of C-S lyase mRNA in the respective renal cells. These results demonstrate that species differences in cisplatin nephrotoxicity are attributable to an interaction of renal Pt transition with C-S lyase activity.
authors.affiliation: Department of Veterinary Basic Medicine, Iwate University, Morioka, Iwate 020-8550, Japan. riekokt@mail.goo.ne.jp
authors.forename: Rieko
authors.initials: R
authors.lastname: Katayama
authors.forename: Saori
authors.initials: S
authors.lastname: Nagata
authors.forename: Hiroko
authors.initials: H
authors.lastname: Iida
authors.forename: Norio
authors.initials: N
authors.lastname: Yamagishi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Furuhama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001483:Base Sequence; D015153:Blotting, Western; D013437:Carbon-Sulfur Lyases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D017931:DNA Primers; D004285:Dogs; D007668:Kidney / Q000187:drug effects*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013045:Species Specificity
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D012333:RNA, Messenger; D013437:Carbon-Sulfur Lyases; C108902:cysteine-S-conjugate beta-lyase; D002945:Cisplatin