Vrzal Radim, Daujat-Chavanieu Martine, Pascussi Jean-Marc, Ulrichova Jitka, Maurel Patrick, Dvorak Zdenek
Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
Eur J Pharmacol. 2008 Mar 10;581(3):244-54. doi: 10.1016/j.ejphar.2007.11.059. Epub 2007 Dec 3.
Disruption of microtubules has been shown to cause suppression of inducibility of major cytochromes P450 (CYP) through several nuclear receptors. Here we tested the effects of structurally different clinically used microtubules-interfering agents (MIAs), such as colchicine, vincristine, vinblastine, nocodazole and taxol on aryl hydrocarbon receptor signaling pathway in human hepatocytes. We show that tested MIAs inhibit 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible expression of CYP1A2 mRNA and restrict TCDD-dependent nuclear translocation of aryl hydrocarbon receptor. On the other hand, these MIAs increased the content of aryl hydrocarbon receptor protein and mRNA by transcriptional mechanism. We show that the MIAs activate c-Jun -N-terminal kinase (JNK), partly p38 but not extracellular-regulated protein kinase (ERK). Consistently, sorbitol, a model activator of JNK, inhibited TCDD-mediated induction of CYP1A2 mRNA and down-regulated tyrosine aminotransferase mRNA - a target gene of glucocorticoid receptor. Dexamethasone had the opposite effect on aryl hydrocarbon receptor signaling and decreased aryl hydrocarbon receptor mRNA and augmented the inducibility of CYP1A2 by TCDD. We conclude that the effects of tested MIAs on aryl hydrocarbon receptor-CYP1A2 signaling pathway are dual, i.e. they inhibit transcriptional activity and nuclear translocation of aryl hydrocarbon receptor but in parallel increase aryl hydrocarbon receptor protein and mRNA level. Microtubules destabilizers have the same effects as stabilizer taxol. This implies that aryl hydrocarbon receptor functions depend on microtubules dynamics but not integrity. Perturbation of aryl hydrocarbon receptor-CYP1A2 signaling by MIAs comprises glucocorticoid receptor-JNK and probably aryl hydrocarbon receptor-JNK/glucocorticoid receptor interactions. We also demonstrate that the effects of MIAs in human hepatocytes do not proceed via arresting cell cycle as confirmed by flow cytometry (FACS) analyses.
微管的破坏已被证明可通过几种核受体导致主要细胞色素P450（CYP）诱导性的抑制。在此，我们测试了结构不同的临床使用的微管干扰剂（MIA），如秋水仙碱、长春新碱、长春花碱、诺考达唑和紫杉醇对人肝细胞中芳烃受体信号通路的影响。我们发现，所测试的MIA抑制2,3,7,8-四氯二苯并对二恶英（TCDD）诱导的CYP1A2 mRNA表达，并限制TCDD依赖的芳烃受体核转位。另一方面，这些MIA通过转录机制增加芳烃受体蛋白和mRNA的含量。我们发现，MIA激活c-Jun氨基末端激酶（JNK），部分激活p38，但不激活细胞外调节蛋白激酶（ERK）。同样，山梨醇作为JNK的模型激活剂，抑制TCDD介导的CYP1A2 mRNA诱导，并下调酪氨酸转氨酶mRNA——糖皮质激素受体的靶基因。地塞米松对芳烃受体信号传导有相反的作用，降低芳烃受体mRNA并增强TCDD对CYP1A2的诱导性。我们得出结论，所测试的MIA对芳烃受体-CYP1A2信号通路的影响是双重的，即它们抑制芳烃受体的转录活性和核转位，但同时增加芳烃受体蛋白和mRNA水平。微管去稳定剂与稳定剂紫杉醇具有相同的作用。这意味着芳烃受体的功能取决于微管动力学而非完整性。MIA对芳烃受体-CYP1A2信号传导的干扰包括糖皮质激素受体-JNK以及可能的芳烃受体-JNK/糖皮质激素受体相互作用。我们还证明，如流式细胞术（FACS）分析所证实的，MIA在人肝细胞中的作用并非通过阻止细胞周期来进行。
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