Nephrotoxicity and covalent binding of 1,1-dichloroethylene in buthionine sulphoximine-treated mice.
Autoradiography of mice injected i.p. with 14C-labelled 1,1-dichloroethylene (vinylidene chloride, VDC) in C57B1/6 mice revealed a selective covalent binding of radioactivity in the proximal tubules, in the midzonal parts of the liver lobules and in the mucosa of the upper and lower respiratory tract. Since VDC is a renal carcinogen in male mice the effects of compounds modulating biotransformation and glutathione (GSH) levels on the renal covalent binding were examined following a single i.p. dose of 14C-VDC. Most pretreatments did not influence the level of binding but treatment with buthionine sulphoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase and glutathione (GSH)-depleting agent, increased the renal covalent binding of VDC three-fold. Histopathological examination of kidneys in BSO-pretreated male mice given single i.p. injections of subtoxic doses of VDC (25 and 50 mg/kg) showed necrosis in the proximal tubules (S1 and S2 segments) 24 h following administration. In mice given VDC only, no significant lesions in the kidneys were observed. The severe renal toxicity of VDC in BSO-pretreated mice is suggested to be related to metabolic activation of VDC in the proximal tubules, resulting in further GSH depletion and covalent binding.
Brittebo
E B
EB
Department of Pharmacology, University of Lund, Sweden.
Darnerud
P O
PO
Eriksson
C
C
Brandt
I
I
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites / Q000187:drug effects; D019328:Buthionine Sulfoximine; D004000:Dichloroethylenes / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009297:Nasal Mucosa / Q000187:drug effects / Q000473:pathology
D004000:Dichloroethylenes; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine