Peroxidative damage and nephrotoxicity of dichlorovinylcysteine in mice.
Male NMRI mice were treated i.p. with dichlorovinylcysteine (DCVC) in a dosage of 2.5-500 mg/kg-1 and renal cortical slices from naive mice were incubated with 0-125 micrograms/ml-1 DCVC. The effects of DCVC on blood urea nitrogen (BUN), reduced glutathione (GSH) content, malondialdehyde (MDA) production, p-aminohippuric acid (PAH)- and tetraethylammonium (TEA)-accumulation and glucose synthesis (gluconeogenesis) were measured. DCVC depleted GSH in a time- and dose-dependent manner. Depletion of renal cortical GSH by DCVC was more pronounced in the kidney cortex than in the liver. DCVC caused a dose-dependent increase of ethane exhalation and of MDA production in the renal cortex. When animals were kept in a closed system, decrease in oxygen concentration increased the peroxidative damage. No increase of MDA concentration was observed in the liver. Treatment of mice with DCVC induced a dose-dependent increase in BUN and decreased the accumulation of PAH and TEA in renal cortical slices. Pretreatment of mice with aminooxyacetic acid (AOAA) and (+) cyanidanol-3 (CY) caused a significant reduction in DCVC-induced lipid peroxidation and nephrotoxicity. In vitro incubation of renal cortical slices of naive mice with DCVC resulted in a concentration-dependent increase in MDA and a concentration-dependent decrease in the accumulations of PAH, TEA and of gluconeogenesis. In conclusion, the interaction of DCVC and/or its metabolites with membrane lipids may be responsible for lipid peroxidation and nephrotoxicity. The formation of lipid peroxidation products was greater under hypoxic conditions and appeared to be related to the DCVC-induced nephrotoxicity. This data suggests lipid peroxidation as a possible mechanism of DCVC-induced nephrotoxicity.
Beuter
W
W
Hoechst AG, Frankfurt/Main, FRG.
Cojocel
C
C
Müller
W
W
Donaubauer
H H
HH
Mayer
D
D
D000818:Animals; D001806:Blood Urea Nitrogen; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D004980:Ethane / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
D013757:Tetraethylammonium Compounds; D008315:Malondialdehyde; C039961:S-(1,2-dichlorovinyl)cysteine; D005978:Glutathione; D003545:Cysteine; D004980:Ethane; D010130:p-Aminohippuric Acid