Abstract

Cytochrome P450 induction is believed to be important in the pathogenesis of alcoholic hepatic disease. Because cimetidine is a general inhibitor of cytochrome P450 enzymes, it was hypothesized that it could be useful in preventing alcoholic hepatic injury. An intragastric feeding model was used these studies. Experimental animals were divided into groups of four to five rats/group and fed the following diets: corn oil+dextrose, corn oil+ethanol (CE) and corn oil+ethanol+cimetidine (250 mg kg-1 day-1) (CEC). The rats in each group were sacrificed at the following time intervals: 2 weeks, 1 month and 2 months. For each animal, the severity of the pathologic findings and relative protein levels of cytochromes P450 2E1, 2B and 4A were measured. In addition, plasma levels of thromboxane B2, 6-ketoprostaglandin F1 alpha and 8-isoprostane were also measured. The most significant finding was that cimetidine completely prevented alcoholic hepatic injury in this model system. The pathologic scores (an indication of the severity of injury) were significantly lower in the CEC groups compared with the CE group. There was however, no significant difference in cytochrome P450 2E1, 2B or 4A protein levels between CE and CEC groups. Thromboxane B2 and 8-isoprostane levels were significantly lower and 6-ketoprostaglandin F1 alpha, significantly higher in the CEC group than in the CE group. These results indicate that possible mechanisms involved in the protective action of cimetidine include inhibition of thromboxane production and lipid peroxidation.