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

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.