CIMETIDINE PREVENTS ALCOHOLIC HEPATIC-INJURY IN THE INTRAGASTRIC FEEDING RAT MODEL

Cytochrome P450 induction is believed to be important in the pathogene sis of alcoholic hepatic disease. Because cimetidine is a general inhi bitor of cytochrome P450 enzymes, it was hypothesized that it could be useful in preventing alcoholic hepatic injury. An intragastric feedin g model was used these studies. Experimental animals were divided into groups of four to five rats/group and fed the following diets: corn o il + dextrose, corn oil + ethanol (CE) and corn oil + ethanol + cimeti dine (250 mg kg(-1) day(-1)) (CEC). The rats in each group were sacrif iced at the following time intervals: 2 weeks, 1 month and 2 months. F or each animal, the severity of the pathologic findings and relative p rotein levels of cytochromes P450 2E1, 28 and 4A were measured. In add ition, plasma levels of thromboxane B-2, 6-ketoprostagiandin F-1 alpha and 8-isoprostane were also measured. The most significant finding wa s that cimetidine completely prevented alcoholic hepatic injury in thi s model system. The pathologic scores (an indication of the severity o f 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. Thromboxa ne B-2 acid 8-isoprostane levels were significantly lower and 6-ketopr ostaglandin F-1 alpha, significantly higher in the CEC group than in t he CE group. These results indicate that possible mechanisms involved in the protective action of cimetidine include inhibition of thromboxa ne production and lipid peroxidation.