Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of human aminopeptidase N

作者：Hausheer F H^*; Parker A R; Petluru P N; Jair K W; Chen S; Huang Q; Chen X; Ayala P Y; Shanmugarajah D; Kochat H

来源：Cancer Chemotherapy and Pharmacology, 2011, 67(2): 381-391.

DOI：10.1007/s00280-010-1333-x

• Aminopeptidase N
• BNP7787
• Chemoprotective agent
• Cisplatin
• Dimesna
• Mesna-disulfide heteroconjugates
• Nephrotoxicity
• Nephrotoxigenic
• Xenobiotic toxification pathway

Previous studies from our laboratory have identified a role for gamma-glutamyl transpeptidase (GGT) in BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate, dimesna, Tavocept (TM))-mediated cisplatin nephroprotection. Dekant has proposed that gamma-glutamyl transpeptidase (GGT), aminopeptidase N (APN) and cysteine-conjugate-beta-lyase (CCBL) comprise a multi-enzyme pathway that acts on xenobiotic-glutathione conjugates converting them to nephrotoxic metabolites. We report modulation of APN activity within this pathway by BNP7787-derived mesna-disulfide heteroconjugates.
A fluorimetric assay was used to determine the effect of BNP7787, BNP7787-derived mesna-disulfide heteroconjugates, and the BNP7787 metabolite, mesna (sodium 2-mercaptoethane sulfonate), on the initial velocity and overall progress curve of the human APN reaction in vitro.
Neither BNP7787 nor mesna-cysteinyl-glutamate inhibited human APN. Select BNP7787-derived mesna-disulfide heteroconjugates (mesna-cysteine, mesna-glutathione, mesna-cysteinyl-glycine) and high concentrations of mesna inhibited APN activity. Allosteric effects on the enzyme progress curve outside of the linear initial velocity region were observed for mesna-cysteinyl-glycine, mesna-glutathione and mesna-cysteinyl-glutamate and appeared to be a function of having both mesna and di- or tri-peptide functionalities in one molecule. In situ-generated mesna-cisplatin conjugates were not a substrate for human APN.
BNP7787-mediated prevention or mitigation of cisplatin-induced nephrotoxicity may involve APN inhibition by certain BNP7787-derived mesna-disulfide heteroconjugates and appears correlated to the presence of a glycinate moiety and/or an anionic group. Two general mechanisms for BNP7787-mediated nephroprotection of cisplatin-induced nephrotoxicity involving the GGT, APN and CCBL nephrotoxigenic pathway are proposed which acting in a concerted and/or synergistic manner, and thereby prevent or mitigate cisplatin-induced renal toxicity.

• 出版日期2011-2