Effects of Cytochrome P450 Inhibition by Cimetidine on the Warm Hepatic Ischemia-Reperfusion Injury in Rats

Abstract

Cimetidine is an H(2)-antagonist with cytochrome P450 (P450) inhibitory activity. Recent studies showed that cimetidine improves warm ischemia-reperfusion (IR) injury in isolated rat heart and rabbit lung and in primary cultures of rat proximal tubule epithelial cells by inhibiting P450-mediated reactive oxygen species generation. Here, we studied the effects of cimetidine on the warm IR injury in the liver. Three groups of rats were treated with a single i.p. dose (0.6 mmol/kg) of cimetidine or ranitidine (an H(2) antagonist without a significant P450 inhibitory activity) or with saline 1.5 h before surgery. Livers were then subjected to 1 h of in vivo ischemia, followed by 1 h of ex vivo reperfusion using a physiologic buffer in a recirculating manner. A fourth group of animals, receiving saline pretreatment underwent sham operation instead of ischemia. Perfusate and bile samples were collected during the reperfusion, and the liver tissue was collected at the end of reperfusion period for measurement of various biochemical markers. Warm IR resulted in a significant increase in the perfusate concentrations of liver enzymes (3- to 4.5-fold) and hepatic concentrations of lipid hydroperoxides (2-fold). Whereas the glutathione concentrations in the liver tissue were not affected by IR injury, the injury caused a significant decrease ( approximately 40%) in the biliary glutathione excretion. Cimetidine treatment completely or partially reversed all the IR-mediated changes, while ranitidine was ineffective. The protective effects of cimetidine were associated with a 60% decline in the microsomal CYP2C11 activity. Whereas cimetidine, an H(2) blocker with substantial P450 inhibitory activity, is protective in warm IR injury, ranitidine, a similar drug with no significant P450 inhibitory activity, is devoid of any protective effects. Therefore, P450 inhibition appears to be the underlying mechanism in the protective effects of cimetidine in this model of IR injury.