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 systems. N-Acetyl-DCVC must be deacetylated before undergoing metabolism by beta-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 beta-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.
Wolfgang
G H
GH
Department of Pharmacology and Toxicology, University of Arizona, Tucson 85724.
Gandolfi
A J
AJ
Stevens
J L
JL
Brendel
K
K
D000107:Acetylation; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D003545:Cysteine / Q000493:pharmacokinetics / Q000633:toxicity / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D007672:Kidney Cortex / Q000187:drug effects* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000293:injuries; D011188:Potassium / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D011817:Rabbits; D010130:p-Aminohippuric Acid / Q000378:metabolism
D006846:Hydrocarbons, Halogenated; D000625:Aminooxyacetic Acid; C039961:S-(1,2-dichlorovinyl)cysteine; D003545:Cysteine; D011339:Probenecid; D011188:Potassium; D010130:p-Aminohippuric Acid