Nephrotoxicity mechanism of cis-platinum (II) diamine dichloride in mice

doi:10.1016/0378-4274(94)90176-7

Toxicology Letters

Volume 71, Issue 2, April 1994, Pages 161-168

https://doi.org/10.1016/0378-4274(94)90176-7 Get rights and content

Abstract

Male Swiss OF1 mice were injected subcutaneously with 20 mg/kg of cis-platinum (II) diamine dichloride (cis-platin). Examination of cryostat kidney sections stained for alkaline phosphatase (APP) revealed damage to about 10, 20, 40 and 50% of the proximal tubules after 7, 24, 48 and 72 h, respectively. Pretreatment with the glutathione synthesis inhibitor, buthionine sulfoximine (BSO), (i.p. 3 mmol/kg) potentiated the tubule damage of cis-platin. In contrast, pretreatment with organic anion transport inhibitor probenecid (i.p. 3 × 0.75 mmol/kg) reduced the number of damaged tubules by approximately 80% at 72 h after cis-platin injection. Pretreatment with the γ-glutamyltranspeptidase (γ-GT) inactivator acivicin (AT-125, 50 mg/kg p.o., plus 50 mg/kg i.p.) failed to prevent cis-platin induced renal toxicity. Pretreatment with the β-lyase inactivator aminooxyacetic acid (AOAA, 2 × 100 mg/kg p.o.) and with the renal cysteine conjugate S-oxidase inhibitor methimazole (40 mg/kg i.p.) reduced the number of damaged tubules by approximately 40% and 75%, respectively in mice treated with cis-platin. The results suggest that the platinum-sulfhydryl group complexes formed are taken up by the kidney cells through an organic anion transport mechanism which is probenecid-sensitive. In the cells these complexes are stable for several hours, depending on the intracellular glutathione (GSH) level, and gradually undergo transformation to reactive metabolite(s) by renal intracellular β-lyase and S-oxidase.

References (31)

R. Safirstein et al.
Cis-platin nephrotoxicity
Amer. J. Kidney Dis.
(1986)
C.R. Hamilton et al.
The late effects of cis-platinum on renal function
Eur. J. Cancer Clin. Oncol.
(1989)
P.C. Dedon et al.
Characterization of the reactions of platinum antitumor agents with biologic and non-biologic sulfur-containing nucleophiles
Biochem. Pharmacol.
(1987)
J. Bongers et al.
Platinum II binding to metallothioneins
J. Inorg. Biochem.
(1988)
C.A.M. Suzuki et al.
The interactions of cis-diamine dichloroplatinum with metallothionein and glutathione in rat liver and kidney
Toxicology
(1990)
M. Ban et al.
Probenecid-induced protection against acute hexachloro-1,3-butadiene and methyl mercury toxicity to the mouse kidney
Toxicol. Lett.
(1988)
J. De Ceaurriz et al.
Role of glutamyltranspeptidase and β-lyase in the nephrotoxicity of hexachloro-1,3-butadiene and methyl mercury in mice
Toxicol. Lett.
(1990)
O.W. Griffith et al.
Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl-homocysteine sulfoximine)
J. Biol. Chem.
(1979)
K. Tsutsui et al.
Chemosensitization by buthionine sulfoxime in vivo
Int. J. Radiat. Oncol. Biol. Phys.
(1986)
E.A. Lock et al.
Effect of the organic acid transport inhibitor probenecid on renal cortical uptake and proximal tubular toxicity of hexachloro-1,3-butadiene and its conjugates
Toxicol. App. Pharmacol.
(1985)

L.H. Lash et al.

Cytotoxicity of S-(1,2-dichlorovinyl)-glutathione and S-(1,2-dichlorovinyl)-l-cysteine in isolated rat kidney cells

J. Biol. Chem.

(1986)

A.A. Elfarra et al.

Renal processing of glutathione conjugates: role in nephrotoxicity

Biochem. Pharmacol.

(1984)

C.E. Merrin

Treatment of genitourinary tumors with cis-dichlorodiamine platinum II: experience in 250 patients

Cancer Treat. Rep.

(1979)

B. Rosenberg et al.

Platinum compounds: a new class of potent antitumor agents

Nature (Lond.)

(1969)

R.C. Young et al.

Cis-dichlorodiamine platinum II for the treatment of advanced ovarian cancer

Cancer Treat. Rep.

(1979)

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Nephrotoxicity mechanism of cis-platinum (II) diamine dichloride in mice

Abstract

Amer. J. Kidney Dis.

Eur. J. Cancer Clin. Oncol.

Biochem. Pharmacol.

J. Inorg. Biochem.

Toxicology

Toxicol. Lett.

Toxicol. Lett.

J. Biol. Chem.

Int. J. Radiat. Oncol. Biol. Phys.

Toxicol. App. Pharmacol.

J. Biol. Chem.

Biochem. Pharmacol.

Treatment of genitourinary tumors with cis-dichlorodiamine platinum II: experience in 250 patients

Cancer Treat. Rep.

Platinum compounds: a new class of potent antitumor agents

Nature (Lond.)

Cis-dichlorodiamine platinum II for the treatment of advanced ovarian cancer

Cancer Treat. Rep.