Species differences in hepatocyte induction of CYP1A1 and CYP1A2 by omeprazole

1 Omeprazole, a proton pump inhibitor therapeutically administered for the treatment of gastric ulcers, induces the expression of cytochromes P4501A1/ 2 (CYP1A1/2) through transcriptional activation mediated by the Ah (dioxin) -receptor. Primary cultures of hepatocytes isolated from rabbit, rat, mouse and human livers were compared for CYP1A1/2 mRNA inducibility by omeprazol e (1 to 100 mu M) 2 Primary cultures of human hepatocytes were the most sensitive to the indu cing effects of omeprazole. Rabbit hepatocytes were the only other cells st udied that showed induced CYP1A1/2 mRNA expression from a concentration low er than 100 mu M (i.e., 10 mu M). Rat hepatocytes were the least sensitive to omeprazole induction. The response of mouse hepatocytes to omeprazole tr eatment was variable, with CYP1A1/2 mRNA expression being induced in only t wo of the three cultures examined. 3 Differences in the time dependence of CYP1A1/2 mRNA expression were obser ved between species. In general, after treatment of hepatocytes with omepra zole the levels of CYP1A1 mRNA peaked prior to that of CYP1A2 mRNA, 4 Due to the interspecific variability of CYP1A mRNA inducibility by omepra zole, we conclude that human hepatocytes in culture are probably the only a ppropriate animal model for prediction of CYP1A induction in humans.