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S-(1,2-dichlorovinyl)-L-cysteine-Induced Nephrotoxicity in the New Zealand White Rabbit: Characterization of Proteinuria and Examination of the Potential Role of Oxidative Injury

Investigative Toxicology Upjohn Laboratories, Kalamazoo, Michigan 49001

David P. Blakeman

Investigative Toxicology Upjohn Laboratories, Kalamazoo, Michigan 49001

Robert A. Jolly

Investigative Toxicology Upjohn Laboratories, Kalamazoo, Michigan 49001

William H. Packwood

Drug Development Toxicology, Upjohn Laboratories, Kalamazoo, Michigan 49001

Gerald J. Kolaja

Drug Development Toxicology, Upjohn Laboratories, Kalamazoo, Michigan 49001

Thomas W. Petry

Investigative Toxicology Upjohn Laboratories, Kalamazoo, Michigan 49001

S-(1,2-dichlorovinyl)-L-cysteine (DCVC)-induced nephrotoxicity in vivo was investigated in New Zealand White rabbits. A primary emphasis in these studies was further characterization of DCVC-induced nephrotoxicity using a variety of serum and urinary analytes, including sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Additionally, the role of oxidative injury was assessed to address the dichotomy between reports indicating that such a mechanism is important in vivo and those indicating that such mechanisms do not contribute substantially to the mechanism of effects observed in vitro. Urine was collected prior to and at 8 and 24 hr after iv administration of DCVC. Serum was collected 15 min prior to and 24 hr after DCVC administration. Rabbits were euthanized 24 hr post-DCVC administration, and kidneys were fixed in formalin and further processed for light microscopic examination.

DCVC (10 mg/kg, iv) induced a 45-50-fold increase in total urinary protein excretion, a 10-15-fold increase in urinary N-acetyl-β-D-glucosaminidase concentration, plus a marked glucosuria by 24 hr postadministration. Additionally, DCVC increased serum creatinine levels by about 2-fold, with a trend toward increased blood urea nitrogen. SDS-PAGE analysis of rabbit urine confirmed the clinical finding of marked proteinuria in DCVC-treated animals, which in contrast to previously reported data was due to the presence of both low and high molecular weight proteins. Antioxidants had no significant effect on DCVC-dependent renal injury, nor was there evidence for DCVC-induced lipid peroxidation, as measured by either thiobarbituric acid-reactive substances or a commercial assay for malondialdehyde and hydroxalkenals. These latter data are consistent with previously published in vitro evidence citing no major role for lipid peroxidation in DCVC-induced nephrotoxicity.

Key Words: Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) • antioxidants • lipid peroxidation • histopathology • clinical chemistries

Toxicologic Pathology, Vol. 23, No. 4, 487-497 (1995)
DOI: 10.1177/019262339502300405


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