Acute effects of the D-isomer of S-(1,2-dichlorovinyl)cysteine on renal function and ultrastructure in the pentobarbital-anesthetized dog: site-specific toxicity involving the S1 and S2 cells of the proximal tubule.
Intravenous doses of 92.6 and 185.2 mumol S-(1,2-dichlorovinyl)-D-cysteine (D-DCVC)/kg were acutely nephrotoxic in pentobarbital-anesthetized dogs. During the 6-h period following administration of either dose, renal arterial blood flow decreased modestly, urinary excretion rate of protein increased, and in contrast to findings in rabbits, ultrastructural lesions developed only in S1 and S2 cells of proximal tubules. The higher dose also induced significant increases in urine flow rate and urinary excretion rate of glucose. The adverse changes noted following the low dose of D-DCVC were due to its direct renal actions and not to extrarenal actions such as major changes in blood gases, total renal blood flow or mean arterial blood pressure that could have indirectly contributed to renal damage via induction of episodes of renal ischemia or hypoxia. In addition, there was a correlation between the proximal tubular cell types injured by D-DCVC and the location of D-amino acid oxidase (DAAO) in the canine nephron. Overall, the nephrotoxicity of D-DCVC was characterized by the same renal function and ultrastructure changes as noted previously with L-DCVC, but the D-isomer was slightly less potent. Our data suggested that the similarity in the toxicity of D- and L-DCVC might be related to DAAO-catalyzed conversion of D-DCVC to the corresponding alpha-ketoacid (DCV-O-MPA) and subsequent biotransformation of the latter to the same highly reactive fragment as generated from the L-isomer.
Krejci
M E
ME
Department of Pharmacology, Medical College of Ohio, Toledo 43699-0008.
Ridgewell
R E
RE
Koechel
D A
DA
D000818:Animals; D001774:Blood Chemical Analysis; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D004285:Dogs; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D008297:Male; D010088:Oxidoreductases / Q000502:physiology; D010424:Pentobarbital; D013237:Stereoisomerism; D014556:Urine / Q000737:chemistry
C039961:S-(1,2-dichlorovinyl)cysteine; D010088:Oxidoreductases; D010424:Pentobarbital; D003545:Cysteine