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首页> 外文期刊>Journal of cellular biochemistry. >Ketoconazole potentiates terfenadine-induced apoptosis in human Hep G2 cells through inhibition of cytochrome p450 3A4 activity.
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Ketoconazole potentiates terfenadine-induced apoptosis in human Hep G2 cells through inhibition of cytochrome p450 3A4 activity.

机译：酮康唑通过抑制细胞色素p450 3A4活性来增强特非那定诱导人Hep G2细胞凋亡。

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Terfenadine (TF) is a highly potent histamine H1 receptor antagonist that in clinically effective doses is free of significant central nervous system side effects. Ketoconazole (KT) is a worldwide used oral antifungal agent with a broad spectrum of activity against both superficial and systemic mycosis. Simultaneously administration of KT and TF has been reported to induce several potent symptoms including cardiotoxicity, excitotoxicity, inhibition of blood mononuclear cells proliferation, and cardiovascular toxicity. However, the intracellular molecular mechanisms of TF-KT interactions in cells were still uncertain. In this study, we first demonstrated that TF (5-30 microM) induced apoptosis in several types of human cancer cell lines including human hepatoma (Hep G2), colorectal cancer (COLO 205), and fibroblast (CCD 922SK) cells for 24 h. The cellular responses to TF-induced apoptosis were demonstrated to be associated with the p53-signaling pathway, including induction of p53, p21/Cip1, p27/Kip1, bax protein expression and inhibition of bcl-2 protein expression. To realized the role of H1 receptor involved in TF-induced apoptosis, different H1 receptor antagonists including promethazine, mequitazine, and chlorpheniramin (50-100 microM) were administered and demonstrated that these chemicals cannot induced apoptosis through the H1 receptor signaling pathway. Interestingly, we found that the apoptotic effect of TF (2.5 microM) was significantly potentiated by KT (1 microM) treatment in Hep G2 cells through inhibition of the cytochrome p450 3A4 (CYP 3A4) activity. Such results were demonstrated by decreased of the TF activity with recombinant CYP 3A4, which prepared from baculovirus-infected insect cells. Our results provide the molecular basis of TF-KT interaction and this information should allow more rational forecasting of the risk for TF therapy during co-administration of KT.
机译：特非那定（TF）是一种高效的组胺H1受体拮抗剂，在临床有效剂量下无明显的中枢神经系统副作用。酮康唑（KT）是一种世界范围内使用的口服抗真菌药，对表浅和全身性真菌病都有广泛的活性。据报道，同时给予KT和TF会诱发多种潜在症状，包括心脏毒性，兴奋性毒性，抑制血液单核细胞增殖和心血管毒性。然而，细胞中TF-KT相互作用的细胞内分子机制仍不确定。在这项研究中，我们首先证明了TF（5-30 microM）在几种类型的人类癌细胞系中诱导凋亡，包括人肝癌（Hep G2），结直肠癌（COLO 205）和成纤维细胞（CCD 922SK）24小时。 。已证明细胞对TF诱导的细胞凋亡的反应与p53信号通路有关，包括诱导p53，p21 / Cip1，p27 / Kip1，bax蛋白表达和抑制bcl-2蛋白表达。为了了解H1受体在TF诱导的细胞凋亡中的作用，已施用了不同的H1受体拮抗剂，包括异丙嗪，美喹他嗪和氯苯那敏（50-100 microM），并证明这些化学物质不能通过H1受体信号传导途径诱导细胞凋亡。有趣的是，我们发现通过抑制细胞色素p450 3A4（CYP 3A4）活性，KT（1 microM）处理可在Hep G2细胞中显着增强TF（2.5 microM）的凋亡作用。通过重组杆状病毒感染的昆虫细胞制备的CYP 3A4降低了TF的活性，从而证明了上述结果。我们的研究结果提供了TF-KT相互作用的分子基础，并且该信息应可以更合理地预测在KT共同给药期间TF治疗的风险。

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