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The capacity for the brain to produce acetaldehyde (AcHO) from ethanol was determined in rat brain homogenates. Rat brains were perfused with saline-heparin solution and homogenized in a phosphate buffer. Varying amounts of tissue were incubated with ethanol (0-100 mM) for periods of up to 60 min. The reaction was stopped by the addition of desferrioxamine and ice-cold perchloric acid. Supernatants were treated with dinitrophenylhydrazine reagent, extracted with isooctane in the presence of an internal standard, and the derivatives were separated by HPLC. The addition of 4-methyl pyrazole (an alcohol dehydrogenase inhibitor) or metyrapone (a cytochrome P450 inhibitor) had no effect on the amount of recovered AcHO. On the other hand, treatment with the catalase inhibitors sodium azide, cyanamide, or 3-amino-1,2,4-triazole blocked the production of AcHO while the addition of exogenous peroxide or a peroxide-generating system enhanced the production of AcHO. Overall, these results suggest that AcHO may be produced in the brain during alcohol intoxication, through the action of the enzyme catalase.

The purpose of this investigation was to assess the effect of chlormethiazole treatment on liver damage in the experimental rat intragastric ethanol-feeding model of alcoholic liver disease. Chlormethiazole has been used in the treatment of alcoholic withdrawal and has been shown to inhibit cytochrome P4502E1. Since treatment of experimental alcoholic liver disease with CYP2E1 inhibitors had an ameliorating effect on liver injury in the rat, chlormethiazole was used to see if it had a similar effect. Rats fed ethanol for 2 months had significantly less liver injury when chlormethiazole was added to the diet, fed intragastrically. The CYP2E1 apoprotein levels, which were increased by ethanol feeding, were also increased when chlormethiazole was fed with ethanol. Chlormethiazole inhibited the increase in the ethanol-induced CYP2E1 activity in vivo, as measured by chlorzoxazone 6-hydroxylation, but did not affect the level of CYP2E1 apoprotein. Likewise, the reduction in proteasome proteolytic enzyme activity produced by ethanol feeding was blunted in chlormethiazole-fed rats. These results support the conclusion that chlormethiazole treatment partially protects the liver from injury by inhibiting CYP2E1 activity in vivo.

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