S-(1,2-dichlorovinyl)-L-cysteine induced cellular injury in rabbit renal cortical slices.
AdvisorGandolfi, A. Jay
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PublisherThe University of Arizona.
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AbstractThe proximal tubule of the kidney is a target for a wide variety of chemical agents, both inorganic and organic. An in vitro model to investigate the site-specific toxicity of organic nephrotoxins was developed and validated using biochemical, functional, and histological parameters. The in vitro toxicity of cephaloridine, gentamicin, hexachloro-butadiene and S-(1,2-dichlorovinyl)-L-cysteine (DCVC) was investigated and the histopathological lesions induced in vitro were compared to those observed in vivo. All four organic nephrotoxins induced a proximal tubular lesion similar to that observed in vivo. DCVC was chosen for additional study. After determining the progression of cellular events resulting from DCVC exposure, the transport, metabolism and localization of DCVC was investigated. DCVC was found to be transported into the proximal tubule via an amino acid system rather than the postulated organic anion system. Aminooxyacetic acid (an inhibitor of β-lyase activity) partially inhibited the covalent binding and toxicity of DCVC indicating that metabolism of DCVC by β-lyase to a reactive thiol is partially responsible for the toxicity. A second enzyme system (L-amino acid oxidase) may play a role in the resulting nephrotoxicity. DCVC is localized to the proximal tubule and mitochondria appear to be the subcellular targets. The site-specific S₃ lesion produced by DCVC may be attributed to innate susceptibility of the S₃ region. The chemical form of a toxin may affect the transport and metabolism of that compound. The N-acetylated derivative of DCVC is an anion and was shown to be transported by the organic anion system. Probenecid, an inhibitor of organic anion transport, almost completely inhibited the toxicity of N-acetyl-DCVC. N-acetyl-DCVC produced a lesion similar to that produced by DCVC. N-acetyl-DCVC is not metabolized by β-lyase and thus must be deacetylated to DCVC prior to being metabolized and producing toxicity. The optical isomer of DCVC, D-DCVC, proved to be less toxic yet exhibited the same selectivity of injury as DCVC. This research demonstrates that an in vitro model which reflects the in vivo toxicity of a compound can be utilized to study the mechanisms (transpoart, metabolism and localization) of selective injury.
Degree ProgramPharmacology and Toxicology