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© 1991 Oxford University Press

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The Acute Effects of S-(1,2-Dichlorovinyl)-L-cysteine and Related Chemicals on Renal Function andUltrastructure in the Pentobarbital-Anesthetized Dog: Structure-Activity Relationships, Biotransformation, and Unique Site-Specific Nephrotoxicity1

DANIEL A. KOECHEL2, MARK E. KREJCI and RICHARD E. RIDGEWELL3

Department of Pharmacology, Medical College of Ohio P.O. Box 10008, Toledo, Ohio 43699-0008

Received June 18, 1990; accepted January 15, 1991

The Acute Effects of S-(l,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. KOECHEL, D. A., KREJCI, M. E., AND RIDGEWELL, R. E. (1991). Fundam Appl. Toxicol. 17, 17-33. S-(l,2-Dichlorovinyl)-L-cysteine (L-DCVC), a substrate for the renal cysteine conjugate ß-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 µmol/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 <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 ß3-lyase (i.e., S-allyl-L-cysteine, vinthionine, and S-(l,2-dichlorovinyl)-D,L-a-methylcysteine) were not acutely nephrotoxic. These findings provide indirect evidence for the involvement of ß-lyase in the toxification of L-DCVC in the dog. 1991 Society of Toxicology.


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