Kikuchi H, Hossain A
Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Exp Toxicol Pathol. 1999 Jul;51(4-5):342-6. doi: 10.1016/S0940-2993(99)80018-9.
Benzimidazole compounds, such as omeprazole and thiabendazole, are a different type of CYP1A1-inducer from Ah receptor-ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene. In HepG2 cells, the commonly used tyrosine kinase-inhibitors, herbimycin-A and a series of tyrphostins, inhibited the induction of CYP1A1 produced by treatment with TCDD. Genistein, another type of tyrosine kinase inhibitor, inhibited the induction of CYP 1A1 whether it was produced by omeprazole or TCDD; however, this inhibition was caused by a dual effect of genistein, that is an anti-tyrosine kinase and an anti-topoisomerase I effect. An antagonist of Ah receptor, 3'-methoxy-4'-aminoflavone (1 microM), did not inhibit the induction of CYP1A1 produced in HepG2 cells by omeprazole or alpha-naphthoflavone (50 microM), but this antagonist did inhibit that produced by TCDD. Thus, omeprazole appears to induce CYP1A1 by initiating a protein tyrosine kinase-mediated signal transduction pathway, a different pathway from that initiated by TCDD.
苯并咪唑化合物，如奥美拉唑和噻苯达唑，是与Ah受体配体（如2,3,7,8-四氯二苯并对二恶英（TCDD）和3-甲基胆蒽）不同类型的CYP1A1诱导剂。在HepG2细胞中，常用的酪氨酸激酶抑制剂、除莠霉素-A和一系列 tyrphostins抑制了TCDD处理产生的CYP1A1的诱导。染料木黄酮，另一种酪氨酸激酶抑制剂，无论CYP 1A1是由奥美拉唑还是TCDD产生，都能抑制其诱导；然而，这种抑制是由染料木黄酮的双重作用引起的，即抗酪氨酸激酶和抗拓扑异构酶I作用。Ah受体拮抗剂3'-甲氧基-4'-氨基黄酮（1 microM）不抑制奥美拉唑或α-萘黄酮（50 microM）在HepG2细胞中产生的CYP1A1的诱导，但该拮抗剂确实抑制TCDD产生的诱导。因此，奥美拉唑似乎通过启动蛋白质酪氨酸激酶介导的信号转导途径来诱导CYP1A1，这是一条与TCDD启动的途径不同的途径。
