Cisplatin nephrotoxicity is mediated by gamma glutamyltranspeptidase, not via a C-S lyase governed biotransformation pathway

Richard D. Wainford, Richard J. Weaver, Keith N. Stewart, Paul Brown, Gabrielle M. Hawksworth

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Cisplatin exhibits dose-limiting nephrotoxicity in rodents and man. This study investigates the mechanism of cisplatin nephrotoxicity in vivo and in an in vitro model system. Nephrotoxicity was induced in rats (6 mg/kg cisplatin i.p.) and mice (10 mg/kg cisplatin i.p.). Cisplatin administration significantly elevated blood urea nitrogen (BUN) and serum creatinine in male Sprague Dawley rats day 5 post-treatment (BUN Delta + 28 +/- 5 mu mol/ml; serum creatinine Delta +/- 1084 nmol/ml, P < 0.05) and in male C57BL6 mice day 4 post-treatment (BUN Delta + 21 +/- 4 mu mol/ml; serum creatinine Delta + 81 +/- 5 nmol/ml, P < 0.05). Nephrotoxicity was confirmed by histological analysis that revealed significant damage to the proximal tubules of cisplatin-versus saline vehicle-treated animals. Inhibition of gamma glutamyltranspeptidase prevented cisplatin nephrotoxicity in Sprague Dawley rats (day 5 BUN Delta + 1 +/- 2 mu mol/ml; serum creatinine A + 8 +/- 4 mu mol/ml) and C57131.6 mice (day 4 BUN Delta + 1 +/- 0.8 mu mol/ml: serum creatinine Delta - 1 +/- 2 nmol/ml), but not cellular toxicity in rat proximal tubular (RPT) or human proximal tubular (HPT) cultures. Inhibition of aminopeptidase N (AP-N) or renal dipeptidase (RDP) in male Sprague Dawley rats, or in RPT and HPT cell cultures, did not reduce cisplatin toxicity. In contrast to published findings inhibition of C-S lyase did not prevent the nephrotoxicity of cisplatin in vivo or cellular toxicity in vitro. These data demonstrate that the biotransformation enzymes AP-N, RDP and C-S Iyase are not implicated in the metabolism of cisplatin to a nephrotoxic metabolite as has been previously hypothesised. Instead, our data demonstrate that gamma glutarnyltranspepticlase is a key enzyme involved in mediating cisplatin nephrotoxicity, which potentially acts to cleave cisplatin-GSH conjugates to a toxic metabolite.(C) 2008 Elsevier Ireland Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)184-193
Number of pages10
JournalToxicology
Volume249
Issue number2-3
Early online date21 May 2008
DOIs
Publication statusPublished - 30 Jul 2008

Keywords

  • cisplatin nephrotoxicity
  • in vivo
  • rat proximal tubular cell cultures
  • human proximal tubular cell cultures
  • proximal tubular cells
  • conjugate beta-lyase
  • transpeptidase-deficient mice
  • glutamyl-transpeptidse
  • primary cultures
  • platinum complexes
  • induced toxicity
  • in-vivo
  • intracellular glutathione
  • liquid-chromatography

Cite this

Cisplatin nephrotoxicity is mediated by gamma glutamyltranspeptidase, not via a C-S lyase governed biotransformation pathway. / Wainford, Richard D.; Weaver, Richard J.; Stewart, Keith N.; Brown, Paul; Hawksworth, Gabrielle M.

In: Toxicology, Vol. 249, No. 2-3, 30.07.2008, p. 184-193.

Research output: Contribution to journalArticle

Wainford, Richard D. ; Weaver, Richard J. ; Stewart, Keith N. ; Brown, Paul ; Hawksworth, Gabrielle M. / Cisplatin nephrotoxicity is mediated by gamma glutamyltranspeptidase, not via a C-S lyase governed biotransformation pathway. In: Toxicology. 2008 ; Vol. 249, No. 2-3. pp. 184-193.
@article{4a7c2496344e42fc91e85e061ed5845e,
title = "Cisplatin nephrotoxicity is mediated by gamma glutamyltranspeptidase, not via a C-S lyase governed biotransformation pathway",
abstract = "Cisplatin exhibits dose-limiting nephrotoxicity in rodents and man. This study investigates the mechanism of cisplatin nephrotoxicity in vivo and in an in vitro model system. Nephrotoxicity was induced in rats (6 mg/kg cisplatin i.p.) and mice (10 mg/kg cisplatin i.p.). Cisplatin administration significantly elevated blood urea nitrogen (BUN) and serum creatinine in male Sprague Dawley rats day 5 post-treatment (BUN Delta + 28 +/- 5 mu mol/ml; serum creatinine Delta +/- 1084 nmol/ml, P < 0.05) and in male C57BL6 mice day 4 post-treatment (BUN Delta + 21 +/- 4 mu mol/ml; serum creatinine Delta + 81 +/- 5 nmol/ml, P < 0.05). Nephrotoxicity was confirmed by histological analysis that revealed significant damage to the proximal tubules of cisplatin-versus saline vehicle-treated animals. Inhibition of gamma glutamyltranspeptidase prevented cisplatin nephrotoxicity in Sprague Dawley rats (day 5 BUN Delta + 1 +/- 2 mu mol/ml; serum creatinine A + 8 +/- 4 mu mol/ml) and C57131.6 mice (day 4 BUN Delta + 1 +/- 0.8 mu mol/ml: serum creatinine Delta - 1 +/- 2 nmol/ml), but not cellular toxicity in rat proximal tubular (RPT) or human proximal tubular (HPT) cultures. Inhibition of aminopeptidase N (AP-N) or renal dipeptidase (RDP) in male Sprague Dawley rats, or in RPT and HPT cell cultures, did not reduce cisplatin toxicity. In contrast to published findings inhibition of C-S lyase did not prevent the nephrotoxicity of cisplatin in vivo or cellular toxicity in vitro. These data demonstrate that the biotransformation enzymes AP-N, RDP and C-S Iyase are not implicated in the metabolism of cisplatin to a nephrotoxic metabolite as has been previously hypothesised. Instead, our data demonstrate that gamma glutarnyltranspepticlase is a key enzyme involved in mediating cisplatin nephrotoxicity, which potentially acts to cleave cisplatin-GSH conjugates to a toxic metabolite.(C) 2008 Elsevier Ireland Ltd. All rights reserved.",
keywords = "cisplatin nephrotoxicity, in vivo, rat proximal tubular cell cultures, human proximal tubular cell cultures, proximal tubular cells, conjugate beta-lyase, transpeptidase-deficient mice, glutamyl-transpeptidse, primary cultures, platinum complexes, induced toxicity, in-vivo, intracellular glutathione, liquid-chromatography",
author = "Wainford, {Richard D.} and Weaver, {Richard J.} and Stewart, {Keith N.} and Paul Brown and Hawksworth, {Gabrielle M.}",
year = "2008",
month = "7",
day = "30",
doi = "10.1016/j.tox.2008.05.006",
language = "English",
volume = "249",
pages = "184--193",
journal = "Toxicology",
issn = "0300-483X",
publisher = "Elsevier Ireland Ltd",
number = "2-3",

}

TY - JOUR

T1 - Cisplatin nephrotoxicity is mediated by gamma glutamyltranspeptidase, not via a C-S lyase governed biotransformation pathway

AU - Wainford, Richard D.

AU - Weaver, Richard J.

AU - Stewart, Keith N.

AU - Brown, Paul

AU - Hawksworth, Gabrielle M.

PY - 2008/7/30

Y1 - 2008/7/30

N2 - Cisplatin exhibits dose-limiting nephrotoxicity in rodents and man. This study investigates the mechanism of cisplatin nephrotoxicity in vivo and in an in vitro model system. Nephrotoxicity was induced in rats (6 mg/kg cisplatin i.p.) and mice (10 mg/kg cisplatin i.p.). Cisplatin administration significantly elevated blood urea nitrogen (BUN) and serum creatinine in male Sprague Dawley rats day 5 post-treatment (BUN Delta + 28 +/- 5 mu mol/ml; serum creatinine Delta +/- 1084 nmol/ml, P < 0.05) and in male C57BL6 mice day 4 post-treatment (BUN Delta + 21 +/- 4 mu mol/ml; serum creatinine Delta + 81 +/- 5 nmol/ml, P < 0.05). Nephrotoxicity was confirmed by histological analysis that revealed significant damage to the proximal tubules of cisplatin-versus saline vehicle-treated animals. Inhibition of gamma glutamyltranspeptidase prevented cisplatin nephrotoxicity in Sprague Dawley rats (day 5 BUN Delta + 1 +/- 2 mu mol/ml; serum creatinine A + 8 +/- 4 mu mol/ml) and C57131.6 mice (day 4 BUN Delta + 1 +/- 0.8 mu mol/ml: serum creatinine Delta - 1 +/- 2 nmol/ml), but not cellular toxicity in rat proximal tubular (RPT) or human proximal tubular (HPT) cultures. Inhibition of aminopeptidase N (AP-N) or renal dipeptidase (RDP) in male Sprague Dawley rats, or in RPT and HPT cell cultures, did not reduce cisplatin toxicity. In contrast to published findings inhibition of C-S lyase did not prevent the nephrotoxicity of cisplatin in vivo or cellular toxicity in vitro. These data demonstrate that the biotransformation enzymes AP-N, RDP and C-S Iyase are not implicated in the metabolism of cisplatin to a nephrotoxic metabolite as has been previously hypothesised. Instead, our data demonstrate that gamma glutarnyltranspepticlase is a key enzyme involved in mediating cisplatin nephrotoxicity, which potentially acts to cleave cisplatin-GSH conjugates to a toxic metabolite.(C) 2008 Elsevier Ireland Ltd. All rights reserved.

AB - Cisplatin exhibits dose-limiting nephrotoxicity in rodents and man. This study investigates the mechanism of cisplatin nephrotoxicity in vivo and in an in vitro model system. Nephrotoxicity was induced in rats (6 mg/kg cisplatin i.p.) and mice (10 mg/kg cisplatin i.p.). Cisplatin administration significantly elevated blood urea nitrogen (BUN) and serum creatinine in male Sprague Dawley rats day 5 post-treatment (BUN Delta + 28 +/- 5 mu mol/ml; serum creatinine Delta +/- 1084 nmol/ml, P < 0.05) and in male C57BL6 mice day 4 post-treatment (BUN Delta + 21 +/- 4 mu mol/ml; serum creatinine Delta + 81 +/- 5 nmol/ml, P < 0.05). Nephrotoxicity was confirmed by histological analysis that revealed significant damage to the proximal tubules of cisplatin-versus saline vehicle-treated animals. Inhibition of gamma glutamyltranspeptidase prevented cisplatin nephrotoxicity in Sprague Dawley rats (day 5 BUN Delta + 1 +/- 2 mu mol/ml; serum creatinine A + 8 +/- 4 mu mol/ml) and C57131.6 mice (day 4 BUN Delta + 1 +/- 0.8 mu mol/ml: serum creatinine Delta - 1 +/- 2 nmol/ml), but not cellular toxicity in rat proximal tubular (RPT) or human proximal tubular (HPT) cultures. Inhibition of aminopeptidase N (AP-N) or renal dipeptidase (RDP) in male Sprague Dawley rats, or in RPT and HPT cell cultures, did not reduce cisplatin toxicity. In contrast to published findings inhibition of C-S lyase did not prevent the nephrotoxicity of cisplatin in vivo or cellular toxicity in vitro. These data demonstrate that the biotransformation enzymes AP-N, RDP and C-S Iyase are not implicated in the metabolism of cisplatin to a nephrotoxic metabolite as has been previously hypothesised. Instead, our data demonstrate that gamma glutarnyltranspepticlase is a key enzyme involved in mediating cisplatin nephrotoxicity, which potentially acts to cleave cisplatin-GSH conjugates to a toxic metabolite.(C) 2008 Elsevier Ireland Ltd. All rights reserved.

KW - cisplatin nephrotoxicity

KW - in vivo

KW - rat proximal tubular cell cultures

KW - human proximal tubular cell cultures

KW - proximal tubular cells

KW - conjugate beta-lyase

KW - transpeptidase-deficient mice

KW - glutamyl-transpeptidse

KW - primary cultures

KW - platinum complexes

KW - induced toxicity

KW - in-vivo

KW - intracellular glutathione

KW - liquid-chromatography

U2 - 10.1016/j.tox.2008.05.006

DO - 10.1016/j.tox.2008.05.006

M3 - Article

VL - 249

SP - 184

EP - 193

JO - Toxicology

JF - Toxicology

SN - 0300-483X

IS - 2-3

ER -