Iron- and ascorbic acid-induced lipid peroxidation in renal microsomes isolated from rats treated with platinum compounds.
Renal microsomes isolated on day 3 from cisplatin (CDDP, single i.p. injection, 4 or 6 mg/kg)-treated rats were monitored for their susceptibility to lipid peroxidation as compared with microsomes from rats treated with carboplatin (CBDCA, 30 mg/kg), transplatin (TDDP, 6 mg/kg) or CDDP hydrolysis products (4 or 6 mg/kg) or from control animals. Cephaloridine (1 g/kg daily for 4 days, i.p. injection) was used as a positive control. The effect of CDDP on renal microsomal glucose-6-phosphatase activity was investigated in vivo and in vitro. Following treatment with CDDP and CDDP hydrolysis products vs CBDCA and TDDP treatment, microsomes revealed an enhanced susceptibility to lipid peroxidation in a Fe2+ and/or ascorbic acid stimulation system. Increased lipid peroxidation, expressed as an increase in malondialdehyde (MDA) generation, paralleled the alterations in body and kidney weight and the elevations of plasma creatinine and blood urea nitrogen concentrations. Injection of the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD, 0.5 g/kg, i.p.) at 24 h prior to CDDP treatment abolished the increased vulnerability of renal microsomes to lipid peroxidation. In vivo, only CDDP hydrolysis products exhibited a significant inhibitory effect on renal glucose-6-phosphatase activity. In vitro, rat renal and hepatic microsomal glucose-6-phosphatase activity was decreased by CDDP both time- and concentration-dependently. Nephrotoxicity induced by CDDP and CDDP hydrolysis products might be attributable to iron-dependent lipid peroxidation and microsomes might represent target organelles on a subcellular level.
Department of Cell Physiology, University Hospital Eppendorf, Hamburg, Federal Republic of Germany.
J
J
Hannemann
J
J
Duwe
K
K
Baumann
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000633:toxicity; D001205:Ascorbic Acid / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology / Q000633:toxicity; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D007501:Iron / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology / Q000633:toxicity; D010984:Platinum / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013997:Time Factors
D000975:Antioxidants; D010655:Phenylenediamines; C034697:transplatin; D010984:Platinum; D016190:Carboplatin; C004845:N,N'-diphenyl-4-phenylenediamine; D007501:Iron; D001205:Ascorbic Acid; D002945:Cisplatin