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-product, has been shown to be metabolized to intermediates that covalently bind to lipids and proteins, and this binding has been associated with trihalomethane-induced renal and hepatic toxicity. In this study, the effects of glutathione (GSH) on in vivo BDCM toxicity and in vitro BDCM macromolecular binding were evaluated. The in vivo toxicity of BDCM in animals pretreated with buthionine sulfoximine (BSO, a glutathione synthesis inhibitor) and in untreated male Fischer 344 rats was investigated. In another experiment, covalent binding to protein and lipid was quantified after [14C]BDCM was incubated with hepatic microsomal and S9 fractions and renal microsomes from F344 rats, under aerobic and anaerobic conditions, with and without added GSH. After oral dosing with BDCM, the BSO-pretreated animals had greatly increased levels of 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 added to an aerobic incubation, protein binding was decreased in hepatic microsomal and S9 fractions by 92 and 83%, respectively. GSH also decreased lipid binding by 55% in hepatic microsomal incubations carried out under anaerobic conditions. Addition of GSH decreased renal microsomal protein (aerobic) and lipid binding (anaerobic) by 20 and 43%, respectively. These data indicate that GSH is an important protective factor in the toxicity associated with BDCM.
Gao
P
P
ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina 27711, USA.
Thornton-Manning
J R
JR
Pegram
R A
RA
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000502:physiology*; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013347:Subcellular Fractions / Q000187:drug effects; D022882:Trihalomethanes
D004791:Enzyme Inhibitors; D006846:Hydrocarbons, Halogenated; D022882:Trihalomethanes; D019328:Buthionine Sulfoximine; C025191:bromodichloromethane; D005978:Glutathione