In vivo potentiation of 1,2-dibromoethane hepatotoxicity by ethanol through inactivation of glutathione-s-transferase.
In the rat, a single ethanol (EtOH) pretreatment (2.5 g/kg b.w., per os) was able to strongly enhance the cytotoxicity of 1,2-dibromoethane (DBE)(87 mg/kg b.w., per os). The principal metabolic routes of DBE involve both oxidative and conjugative transformations. Microsomal cytochrome P450 content and dimethyl nitrosamine demethylase activity were not changed, while a significant loss of cytosolic total GSH-transferase was observed in rats killed 6 h after EtOH pretreatment. Pretreatment with methylpyrazole, an inhibitor of alcohol-dehydrogenase prevented the effects provoked by ethanol. The major EtOH metabolite, acetaldehyde. seemed thus to play a fundamental role in the mechanism responsible for the potentiation of DBE toxicity mediated by EtOH. To further support this hypothesis, disulfiram (75 mg/kg b.w.), an inhibitor of aldehyde dehydrogenase, was given i.p. to rats. When DBE was administered to disulfiram- and EtOH-pretreated rats, a marked increase of liver cytolysis was shown and cytosolic GSH-transferase activity was further inhibited if compared to that induced by EtOH treatment alone. The results are consistent with the hypothesis that EtOH given to rats increases DBE liver toxicity because its major metabolite, acetaldehyde, reduces the DBE conjugates to GSH transferase, with consequent shift of DBE metabolism to the oxidative route and accumulation of reactive oxidative intermediates no longer effectively conjugated with GSH.
Aragno
M
M
CNR Centre of Immunogenetics and Experimental Oncology, Torino, Italy.
Tamagno
E
E
Danni
O
O
Chiarpotto
E
E
Biasi
F
F
Scavazza
A
A
Albano
E
E
Poli
G
G
Dianzani
M U
MU
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015946:Ethylene Dibromide / Q000494:pharmacology* / Q000633:toxicity*; D000077604:Fomepizole; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D011720:Pyrazoles; D015946:Ethylene Dibromide; D000431:Ethanol; D008315:Malondialdehyde; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; D000426:Alcohol Dehydrogenase; D007064:L-Iditol 2-Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D005982:Glutathione Transferase; D005978:Glutathione; D004221:Disulfiram