Curi-Pedrosa R, Daujat M, Pichard L, Ourlin J C, Clair P, Gervot L, Lesca P, Domergue J, Joyeux H, Fourtanier G
Institut National de la Santé et de la Recherche Médicale U-128, Centre National de la Recherche Scientifique, Montpellier, France.
J Pharmacol Exp Ther. 1994 Apr;269(1):384-92.
The ability of several gastric antiulcer drugs including lansoprazole, cimetidine and ranitidine to affect the expression of human liver microsomal cytochromes P450 comparatively to omeprazole, reported previously to be a CYP1A inducer, was evaluated in primary cultures of human hepatocytes. Poly (A)+ RNA and microsomes extracted from the cells were analyzed in Northern and Western blots with specific cDNA probes and antibodies, and assayed for form-specific monoxygenase activities. Lansoprazole induced both CYP1A1 and CYP1A2 as omeprazole and did not apparently bind to the aryl hydrocarbon receptor with high affinity. Omeprazole sulfone was not an inducer of CYP1A. Omeprazole, omeprazole sulfone and lansoprazole induced CYP3A in approximately 50% of tested cultures, whereas 100% of tested cultures responded to omeprazole and to rifampicin in terms of CYP1A and CYP3A induction, respectively. Finally, cimetidine and ranitidine were not inducers. We conclude that omeprazole and lansoprazole constitute a new class of mixed inducers of CYP1A and CYP3A in human hepatocytes in primary culture and that the induction of CYP3A in response to these molecules could be polymorphic in humans.
在原代培养的人肝细胞中，评估了包括兰索拉唑、西咪替丁和雷尼替丁在内的几种胃抗溃疡药物与先前报道为CYP1A诱导剂的奥美拉唑相比，对人肝微粒体细胞色素P450表达的影响。从细胞中提取的聚腺苷酸（Poly (A)+）RNA和微粒体，用特异性cDNA探针和抗体进行Northern印迹和Western印迹分析，并检测其形式特异性单加氧酶活性。兰索拉唑与奥美拉唑一样，可诱导CYP1A1和CYP1A2，且显然不会以高亲和力与芳烃受体结合。奥美拉唑砜不是CYP1A的诱导剂。奥美拉唑、奥美拉唑砜和兰索拉唑在大约50%的受试培养物中诱导CYP3A，而在CYP1A和CYP3A诱导方面，分别有100%的受试培养物对奥美拉唑和利福平有反应。最后，西咪替丁和雷尼替丁不是诱导剂。我们得出结论，奥美拉唑和兰索拉唑在原代培养的人肝细胞中构成了一类新的CYP1A和CYP3A混合诱导剂，并且人类对这些分子的CYP3A诱导可能具有多态性。
