PROTECTIVE EFFECTS OF GLUTATHIONE ON BROMODICHLOROMETHANE IN-VIVO TOXICITY AND IN-VITRO MACROMOLECULAR BINDING IN FISCHER-344 RATS

Bromodichloromethane (BDCM), a carcinogenic water disinfection by-prod uct, has been shown to be metabolized to intermediates that covalently bind to lipids and proteins, and this binding has been associated wit h trihalomethane-induced renal and hepatic toxicity. In this study, th e effects of glutathione (GSH) on in vivo BDCM toxicity and in vitro B DCM macromolecular binding were evaluated. The in vivo toxicity of BDC M in animals pretreated with buthionine sulfoximine (BSO, a glutathion e synthesis inhibitor) and in untreated male Fischer 344 rats was inve stigated. In another experiment, covalent binding to protein and lipid was quantified after [(1)4C]BDCM was incubated with hepatic microsoma l and S9 fractions and renal microsomes from F344 rats, under aerobic and anaerobic conditions, with and without added GSH. After oral dosin g with BDCM, the BSO-pretreated animals had greatly increased levels o f serum indicators of hepatotoxicity and serum and urinary indicators of nephrotoxicity compared to those in animals dosed solely with BDCM. Histopathological examination revealed that hepatic necrosis was more severe than renal necrosis in the BSO-treated rats. When GSH was adde d to an aerobic incubation, protein binding was decreased in hepatic m icrosomal and S9 fractions by 92 and 83%, respectively. GSH also decre ased lipid binding by 55% in hepatic microsomal incubations carried ou t under anaerobic conditions. Addition of GSH decreased renal microsom al protein (aerobic) and lipid binding (anaerobic) by 20 and 43%, resp ectively. These data indicate that GSH is an important protective fact or in the toxicity associated with BDCM.