Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol
✍ Scribed by E Albano; P Clot; M Morimoto; A Tomasi; M Ingelman-Sundberg; S W French
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 257 KB
- Volume
- 23
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
alcohol feeding and that ethanol-derived free radicals We have previously shown that the treatment with might play a role in the onset of liver injury in this model diallyl sulfide (DAS) and phenylethyl isothiocyanate of alcohol administration. (HEPATOLOGY 1996;23:155-(PIC) of rats receiving ethanol in the alcohol tube-feed-163.) ing model effectively suppressed the induction of cytochrome P4502E1 (CYP2E1) by ethanol. Here we report that rat treatment with DAS and PIC significantly de-
In recent years the possible involvement of free radicreased the trapping of hydroxyethyl free radicals in cal mediated oxidative injury in the pathogenesis of liver microsomes incubated in vitro with ethanol. Furalcohol-induced liver diseases has received increasing thermore, these inhibitors also greatly reduced the proattention. 1 Clinical studies have shown that products duction of hydroxyethyl radical-derived epitopes detectof lipid peroxidation can be detected in the liver and able in vivo in the liver of ethanol-fed rats. The action of in the blood of heavy drinkers 2,3 and that peroxidative DAS and PIC on the formation of hydroxyethyl radicals damage increases with the amount of ethanol conparalleled their inhibitory effect on lipid peroxidation as monitored using, respectively, liver malonildialdehyde sumed. 4 These observations have recently found an ex-(MDA) and plasma lipid hydroperoxide levels as well as perimental support by the use of intragastric tube feedby the titers of antibodies versus MDA adducts to proing model of chronic ethanol administration, which has teins. Thus, these results indicated a link between the allowed investigations in the relationship between the induction of CYP2E1 by ethanol, the formation of hyevidence of oxidative damage and the development of droxyethyl radicals and the stimulation of lipid peroxiliver injury. [5][6][7][8][9] dation. The pathological scores in the livers of rats fed Using this model we have observed that the inducwith ethanol plus or minus DAS and PIC also correlated tion of cytochrome P4502E1 (CYP2E1) by ethanol was with levels of hydroxyethyl radical-derived epitopes.
associated with an increase of lipid peroxidation, which Rats fed intragastrically with ethanol developed antiwas detectable both in vitro and in vivo. 6,7 Moreover, bodies reacting with hydroxyethyl radicals-modified proteins and the formation of these antibodies was the treatment of rats with diallyl sulfide (DAS) or phegreatly reduced by DAS and PIC. Taken together these nylethyl isothiocyanate (PIC), which inhibited CYP2E1 results suggest that CYP2E1 plays an important role in expression, strongly decreased lipid peroxidation meathe generation of hydroxyethyl radicals during chronic sured in vitro in liver microsomes as well as in vivo in the plasma of alcohol-fed animals. 10 Interestingly, among these animals a positive correlation was evident Abbreviations: CYP2E1, cytochrome P450 2E1; DAS, diallyl sulfide; PIC, between the histological evidence of liver injury (i.e., phenylethyl isothiocyanate; KLH, keyhole limpet hemocyanin; RSA, rat serum steatosis, inflammation, and necrosis) and the liver albumin; Ig, immunoglobulin; 4-POBN, 4-pyridyl-1-oxide-t-butyl nitrone;