Dichlorovinyl cysteine (DCVC) in the mouse kidney: tissue-binding and toxicity after glutathione depletion and probenecid treatment.
The kidney binding of dichloro[14C]vinyl cysteine (14C-DCVC, 8 mg/kg body wt) and the kidney histopathology of DCVC (5 mg/kg body wt) were examined and compared in female C57BL mice subjected to various treatments. To evaluate the roles of organic anion transport and glutathione (GSH) status, mice were pretreated with probenecid (inhibitor of organic anion transport), L-buthionine-S,R-sulfoximine (BSO; inhibitor of GSH synthesis) or with diethyl maleate (DEM; GSH-depleting agent). In addition, the sites of 14C-DCVC binding in BSO-treated and control mice were monitored by microautoradiography. Probenecid was found to inhibit both kidney binding and toxicity of DCVC. In BSO-treated mice, DCVC binding remained roughly unchanged, whereas nephrotoxicity was severely increased and topographically extended to the subcapsular region. Microautoradiography showed that the site of DCVC binding in the straight portion of the proximal tubule was not changed by BSO. In DEM-treated mice, a clearly decreased DCVC binding was observed, while the effect on nephrotoxicity was minute. The effects of probenecid on DCVC binding and toxicity support a role for carrier-mediated transport of DCVC equivalents into the target cells. The BSO result suggests a protective function of GSH towards the nephrotoxicity of DCVC. Moreover, they support our previous contention that a primary lesion occurs at the site of DCVC binding, followed by a secondary, dose-dependent lesion localized outside the DCVC-binding region. In the case of DEM it is proposed that a DEM-GSH conjugate might compete for the uptake and/or activation of DCVC in the target cells.
Darnerud
P O
PO
Dept of Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala Biomedical Centre.
Brandt
I
I
Feil
V J
VJ
Bakke
J E
JE
D000818:Animals; D001345:Autoradiography; D003545:Cysteine / Q000378:metabolism / Q000031:analogs & derivatives; D005260:Female; D005978:Glutathione / Q000502:physiology*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011339:Probenecid / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism
D013438:Sulfhydryl Compounds; C039961:S-(1,2-dichlorovinyl)cysteine; D005978:Glutathione; D003545:Cysteine; D011339:Probenecid