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01.02.2011 | Original Article

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

verfasst von: 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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2011

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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 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.

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.

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Titel: Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of human aminopeptidase N
verfasst von: 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
Publikationsdatum: 01.02.2011
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2011
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1333-x

Springer Medizin

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