The acute effects of S-(1,2-dichlorovinyl)-L-cysteine and related chemicals on renal function and ultrastructure in the pentobarbital-anesthetized dog: structure-activity relationships, biotransformation, and unique site-specific nephrotoxicity.
S-(1,2-Dichlorovinyl)-L-cysteine (L-DCVC), a substrate for the renal cysteine conjugate beta-lyase, and other related chemicals were administered intravenously to pentobarbital-anesthetized dogs. Six pertinent findings emerged regarding their nephrotoxicity. (1) L-DCVC was acutely nephrotoxic in the dog. (2) The earliest indicator of L-DCVC-induced renal damage was an increase in the urinary excretion rate of protein. (3) Contrary to results from other species, L-DCVC induced renal ultrastructural lesions only in the S1 and S2 cells of the proximal tubule. (4) The toxicity of L-DCVC (23.15 mumol/kg, iv) to S1 and S2 cells resulted from a direct tubular insult and not from overlapping episodes of hypoxia or ischemia. (5) L-DCVC could be detected in plasma only during the first 30 min after its injection. In addition, no L-DCVC and only small amounts of N-acetyl-L-DCVC and S-(1,2-dichlorovinyl)mercaptoacetic acid (DCV-MAA) (1.5% and less than 1% of the administered dose, respectively) were detectable in urine during the 6 hr following L-DCVC administration. (6) DCV-MAA and chloroacetic acid as well as other compounds that are not substrates for the renal cysteine conjugate beta-lyase (i.e., S-allyl-L-cysteine, vinthionine, and S-(1,2-dichlorovinyl)-D,L-alpha-methylcysteine) were not acutely nephrotoxic. These findings provide indirect evidence for the involvement of beta-lyase in the toxification of L-DCVC in the dog.
Department of Pharmacology, Medical College of Ohio, Toledo 43699-0008.
D A
DA
Koechel
M E
ME
Krejci
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Ridgewell
D000758:Anesthesia; D000818:Animals; D001711:Biotransformation; D013437:Carbon-Sulfur Lyases; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004285:Dogs; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology; D008190:Lyases / Q000378:metabolism; D008297:Male; D010424:Pentobarbital; D012121:Respiration, Artificial; D013329:Structure-Activity Relationship; D014563:Urodynamics / Q000187:drug effects
C039961:S-(1,2-dichlorovinyl)cysteine; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D010424:Pentobarbital; D003545:Cysteine