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

F. H. Hausheer, A. R. Parker, P. N. Petluru, K. W. Jair, S. Chen, Q. Huang, X. Chen, P. Y. Ayala, D. Shanmugarajah, H. Kochat

Research output: Contribution to journalArticle

Abstract

Purpose: 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)-mediated cisplatin nephroprotection. Dekant has proposed that gamma-glutamyl transpeptidase (GGT), aminopeptidase N (APN) and cysteine-conjugate-β-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. Methods: 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. Results: Neither BNP7787 nor mesna-cysteinyl-glutamate inhibited human APN. Select BNP7787-derived mesnadisulfide 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, mesnaglutathione 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 mesnacisplatin conjugates were not a substrate for human APN. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)381-391
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume67
Issue number2
DOIs
StatePublished - Feb 2011
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

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  • Cite this

    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. (2011). Mechanistic study of BNP7787-mediated cisplatin nephroprotection: Modulation of human aminopeptidase N. Cancer Chemotherapy and Pharmacology, 67(2), 381-391. https://doi.org/10.1007/s00280-010-1333-x