NEPHROTOXICITY AND COVALENT BINDING OF 1,1-DICHLOROETHYLENE IN BUTHIONINE SULFOXIMINE-TREATED MICE

Autoradiography of mice injected i.p. with C-14-labelled 1,1-dichloroe thylene (vinylidene chloride, VDC) in C57B1/6 mice revealed a selectiv e covalent binding of radioactivity in the proximal tubules, in the mi dzonal parts of the liver lobules and in the mucosa of the upper and l ower respiratory tract. Since VDC is a renal carcinogen in male mice t he effects of compounds modulating biotransformation and glutathione ( GSH) levels on the renal covalent binding were examined following a si ngle i.p. dose of C-14-VDC. Most pretreatments did not influence the l evel of binding but treatment with buthionine sulphoximine (BSO), an i rreversible inhibitor of gamma-glutamylcysteine synthetase and glutath ione (GSH)-depleting agent, increased the renal covalent binding of VD C three-fold. Histopathological examination of kidneys in BSO-pretreat ed 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 segm ents) 24 h following administration. In mice given VDC only, no signif icant 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 de pletion and covalent binding.