Štěpánková Martina, Krasulová Kristýna, Dořičáková Aneta, Kurka Ondřej, Anzenbacher Pavel, Dvořák Zdeněk
Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czechia.
Institute of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czechia; Institute of Molecular and Translational Medicine, Faculty of Medicine, Palacky University at Olomouc, Hnevotinska 5, 775 15 Olomouc, Czechia.
Toxicol Lett. 2016 Nov 16;262:173-186. doi: 10.1016/j.toxlet.2016.10.005. Epub 2016 Oct 11.
Dihydropyridine calcium channel blockers (CCBs) are used as anti-hypertensives and in the treatment of angina pectoris. Structurally, CCBs have at least one chiral center in the molecule, thereby existing in two or more different enantiomers. In the current paper we examined effects of benidipine, felodipine and isradipine enantiomers on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450. All CCBs dose-dependently activated aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR), as revealed by gene reporter assays. Activation of AhR, but not PXR, was enantiospecific. Consistently, CCBs induced CYP1A1 and CYP1A2 mRNAs, but not protein, in human hepatocytes and HepG2 cells, with following pattern: benidipine (-)>(+), isradipine (-)>(+) and felodipine (+)>(-). All CCBs induced CYP2A6, CYP2B6 and CYP3A4 mRNA and protein in human hepatocytes, and there were not differences between the enantiomers. All CCBs transformed AhR in its DNA-binding form, as revealed by electromobility shift assay. Tested CCBs inhibited enzyme activities of CYP3A4 (benidipine (+)>(-); felodipine (-)>(+); isradipine (-)-(+)) and CYP2C9 (benidipine (-)>(+); felodipine (+)>(-); isradipine (-)>(+)). The data presented here might be of toxicological and clinical importance.
二氢吡啶类钙通道阻滞剂（CCBs）被用作抗高血压药物以及用于治疗心绞痛。从结构上看，CCBs分子中至少有一个手性中心，因此以两种或更多种不同的对映体形式存在。在本论文中，我们研究了贝尼地平、非洛地平和伊拉地平对映体对人外源物质代谢细胞色素P450的表达和酶活性的影响。基因报告分析显示，所有CCBs均呈剂量依赖性地激活芳烃受体（AhR）和孕烷X受体（PXR）。AhR的激活具有对映体特异性，而PXR的激活则不然。同样，CCBs在人肝细胞和HepG2细胞中诱导CYP1A1和CYP1A2 mRNA，但不诱导蛋白质，其诱导模式如下：贝尼地平（-）>（+），伊拉地平（-）>（+），非洛地平（+）>（-）。所有CCBs在人肝细胞中均诱导CYP2A6、CYP2B6和CYP3A4 mRNA及蛋白质，且对映体之间无差异。电泳迁移率变动分析显示，所有CCBs均将AhR转化为其DNA结合形式。所测试的CCBs抑制CYP3A4（贝尼地平（+）>（-）；非洛地平（-）>（+）；伊拉地平（-）-（+））和CYP2C9（贝尼地平（-）>（+）；非洛地平（+）>（-）；伊拉地平（-）>（+））的酶活性。本文所呈现的数据可能具有毒理学和临床重要性。
