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首页> 外文期刊>Life sciences >The role of protein tyrosine kinases in CYP1A1 induction by omeprazole and thiabendazole in rat hepatocytes
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The role of protein tyrosine kinases in CYP1A1 induction by omeprazole and thiabendazole in rat hepatocytes

机译：蛋白酪氨酸激酶在奥美拉唑和噻菌灵诱导大鼠肝细胞CYP1A1中的作用

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Benzimidazoles compounds like omeprazole (OME) and thiabendazole (TBZ) mediate CYP1A1 induction differently from classical aryl hydrocarbon receptor (AhR) ligands, 3-methylcholanthrene (3-MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). To clarify the involvement of an intracellular signal pathway in CYP1A1 induction by OME and TBZ, the TBZ, OME and 3-MC signal-transducing pathways were compared by using specific protein tyrosine kinase inhibitors in primary culture of rat hepatocytes. The effect of OME and TBZ (75-250 muM) on cytochrome P450 1A1 (CYP1A1) expression was therefore studied in primary cultures of rat hepatocytes after 24 h, 48 h and 72 h of exposure. Both compounds provoked a dose- and time-dependent increase in CYP1A1 (EROD activity, protein and mRNA levels), but OME was less effective at all the concentrations and times tested. The mechanism of benzimidazole-mediated induction of CYP1A1 was investigated by comparison with 3-MC, a prototypical AhR ligand. As expected, OME and TBZ were unable to displace [H-3]-TCDD from its binding sites to the AhR in competitive binding studies. Moreover, classic tyrosine kinase inhibitor herbimycin A (HA) inhibited the two benzimidazoles-mediated CYP1A1 inductions, but only partially inhibited the 3-MC-mediated one. Another two tyrosine kinase inhibitors, lavendustin A (LA) and genistein (GEN), had no effect on CYP1A1 induction by benzimidazoles and 3-MC. These results are consistent with the implication of a tyrosine kinase, most probably the Src tyrosine kinase, in the mechanism of CYP1A1 induction in rat hepatocytes. (C) 2004 Elsevier Inc. All rights reserved. [References: 38]
机译：苯并咪唑类化合物如奥美拉唑（OME）和噻苯达唑（TBZ）介导的CYP1A1诱导作用不同于经典的芳烃受体（AhR）配体，3-甲基胆碱（3-MC）和2,3,7,8-四氯二苯并-对-二恶英（TCDD） ）。为了阐明OME和TBZ诱导CYP1A1诱导细胞内信号途径的参与，通过在大鼠肝细胞的原代培养中使用特定的蛋白酪氨酸激酶抑制剂比较了TBZ，OME和3-MC信号转导途径。因此，在暴露后24、48和72小时的大鼠肝细胞原代培养中研究了OME和TBZ（75-250μM）对细胞色素P450 1A1（CYP1A1）表达的影响。两种化合物均引起CYP1A1的剂量和时间依赖性增加（EROD活性，蛋白质和mRNA水平），但在所有测试的浓度和时间，OME的效果均较差。通过与原型AhR配体3-MC的比较，研究了苯并咪唑介导的CYP1A1诱导的机制。不出所料，在竞争性结合研究中，OME和TBZ无法将[H-3] -TCDD从其结合位点转移至AhR。此外，经典的酪氨酸激酶抑制剂除草霉素A（HA）抑制了两种苯并咪唑介导的CYP1A1诱导，但仅部分抑制了3-MC介导的CYP1A1诱导。另外两种酪氨酸激酶抑制剂lavendustin A（LA）和染料木黄酮（GEN）对苯并咪唑和3-MC诱导的CYP1A1无效。这些结果与酪氨酸激酶（最可能是Src酪氨酸激酶）在大鼠肝细胞中CYP1A1诱导机制中的意义一致。 （C）2004 Elsevier Inc.保留所有权利。 [参考：38]

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