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.
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-beta-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Davis
J W
JW
Investigative Toxicology, Upjohn Laboratories, Kalamazoo, Michigan 49001, USA.
Blakeman
D P
DP
Jolly
R A
RA
Packwood
W H
WH
Kolaja
G J
GJ
Petry
T W
TW
D000118:Acetylglucosaminidase / Q000032:analysis; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D004591:Electrophoresis, Polyacrylamide Gel; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D011507:Proteinuria / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011817:Rabbits
D000975:Antioxidants; C039961:S-(1,2-dichlorovinyl)cysteine; D000118:Acetylglucosaminidase; D003545:Cysteine