Assessment of S-(1,2-dichlorovinyl)-L-cysteine induced toxic events in rabbit renal cortical slices. Biochemical and histological evaluation of uptake, covalent binding, and toxicity.
A renal cortical slice system was utilized to investigate the events leading to site-specific nephrotoxicity induced by S-(1,2-dichlorovinyl)-L-cysteine (DCVC). DCVC uptake into renal cortical slices was shown to be rapid (5-15 min) as well as time- and concentration-dependent. Of the total amount taken up at 1 h, 40% was subsequently covalently bound. These observations were confirmed by autoradiography, illustrating uptake and binding in the proximal tubule cells. Following these events, toxicity was evidenced by alterations in ATP content and O2 consumption between 4 and 8 h as well as leakage of the brush border enzymes (gamma glutamyl transpeptidase and alkaline phosphatase) as early as 4 h. Light microscopy provided a sequence of histopathological changes from an initial S3 lesion between 4 and 8 h to a lesion encompassing all proximal tubule segments (by 12 h). Electron microscopy demonstrated not only the specificity of DCVC toxicity (at 6 h) but also illustrated mitochondrial damage and loss of brush borders. A comparison of continuous versus short-term exposure to DCVC indicated that an irreversible sequence of events was initiated as early as 30 min. By utilizing an in vitro model which allows correlation of biochemical and histological changes, a sequence of events leading to DCVC induced toxicity was established.
Wolfgang
G H
GH
Department of Pharmacology and Toxicology, University of Arizona, Tucson 85724.
Gandolfi
A J
AJ
Nagle
R B
RB
Brendel
K
K
Stevens
J L
JL
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008190:Lyases / Q000032:analysis; D008928:Mitochondria / Q000187:drug effects; D011817:Rabbits
C039961:S-(1,2-dichlorovinyl)cysteine; D008190:Lyases; D003545:Cysteine