N-acetyl S-(1,2-dichlorovinyl)-l-cysteine produces a similar toxicity to S-(1,2-dichlorovinyl)-l-cysteine in rabbit renal slices: differential transport and metabolism

Grushenka H.I. Wolfgang, A. Jay Gandolfi, James L. Stevens, Klaus Brendel

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Renal cortical slices were used to determine the toxicity of N-acetyl S-(1,2-dichlorovinyl)-l-cysteine (N-acetyl-DCVC) as well as to investigate the transport and metabolism of S-(1,2-dichlorovinyl)-l-cysteine (DCVC) and the N-acetyl derivative. N-Acetyl-DCVC produced dose- and time-dependent decreases in intracellular K+ content and lactate dehydrogenase activity. Histopathology demonstrated an initial S3 lesion followed by a lesion inclusive of all proximal tubules. N-Acetyl-DCVC was shown to be transported via the organic anion system by its ability to inhibit PAH transport by the cells and the ability of probenecid to decrease uptake (80%) and toxicity of N-acetyl-DCVC. DCVC, in contrast, was not transported by the organic anion system, but may be transported by one or more amino acid system. N-Acetyl-DCVC must be deacetylated before undergoing metabolism by β-lyase. This process must occur since covalent binding of a 35S-labeled reactive product from N-acetyl[35S]DCVC is observed within 1 hr. Both the uptake inhibitor, probenecid, and aminooxyacetic acid (AOAA), a β-lyase inhibitor, decreased the covalent binding from N-acetyl[35S]DCVC (80 and 50%, respectively), but only AOAA inhibited the covalent binding of DCVC. AOAA also partially inhibited the toxicity of DCVC and N-acetyl-DCVC as determined by intracellular K+ content, lactate dehydrogenase activity, and histopathology. Despite the fact that a separate transport system and an additional enzymatic step (deacetylation) are required, N-acetyl-DCVC produces a lesion with similar intratubular specificity to that seen with DCVC. Therefore, the S3 specificity seen in vivo could be produced by either compound.

Original languageEnglish (US)
Pages (from-to)205-219
Number of pages15
JournalToxicology and Applied Pharmacology
Volume101
Issue number2
DOIs
StatePublished - Nov 1989
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint Dive into the research topics of 'N-acetyl S-(1,2-dichlorovinyl)-l-cysteine produces a similar toxicity to S-(1,2-dichlorovinyl)-l-cysteine in rabbit renal slices: differential transport and metabolism'. Together they form a unique fingerprint.

  • Cite this