Résumé
Omeprazole is a new drug used for its high efficiency as an inhibitor of gastric acid secretion. This substituted benzimidazole molecule had been shown to decrease several liver cytochrome P450-mediated monooxygenase activities both in vitro and in vivo. The present work was undertaken to determine whether this drug was an inducer of cytochrome P450 in humans. Primary cultures of human hepatocytes were maintained in a serum-free, chemically defined medium for 0–96 hours in the absence or in the presence of omeprazole (1–100 μmol/L) or of other cytochrome P450 inducers such as 3-methylcholanthrene, β-naphthoflavone, or rifampicin for comparison. Omeprazole produced a time- and concentration-dependent increase in (a) cytochrome P450IA2 accumulation determined by western blot in microsomes from omeprazole-treated cells, while the level of other cytochrome P450 forms including P450IID6, IIE1, and IIIA was not increased in the same culture; (b) several monoxygenase activities, including phenacetin deethylase and acetanilide hydroxylase (cytochrome P450IA2) and ethoxyresorufin deethylase and benzpyrene hydroxylase (cytochrome P450IA1); (c) cytochrome P450IA2 de novo synthesis, determined by immunoprecipitation of cell lysate from [3H]Leu-Iabeled cells; (d) cytochromes P450IA1 and IA2 mRNAs, determined by northern blot analysis. An in vivo study was carried out on liver microsomes from five patients for whom hepatic biopsy specimens were available before and after repeated administration of omeprazole (20 mg/day for 4 days). In all cases, several-fold increases in cytochrome P450IA2 and specific cytochrome P450IA subfamily-dependent monooxygenase activities were observed in agreement with the results from cell culture. It was concluded that omeprazole is an aryl hydrocarbon-like inducer of cytochrome P450 secretion in human liver both in vitro and in vivo. This drug is therefore likely to increase the metabolism of any xenobiotic specifically oxidized by a cytochrome P450IA subfamily. This could potentiate the hepatotoxicity of phenacetin or paracetamol and activation of procarcinogens.