title: Optical isomers of dihydropyridine calcium channel blockers display enantiospecific effects on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450.
abstract: 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.
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czechia.
authors.forename: Martina
authors.initials: M
authors.lastname: Štěpánková
authors.affiliation: 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.
authors.forename: Kristýna
authors.initials: K
authors.lastname: Krasulová
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czechia.
authors.forename: Aneta
authors.initials: A
authors.lastname: Dořičáková
authors.affiliation: Department of Analytical Chemistry, Regional Centre of Advanced Technologies and Materials Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czechia.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Kurka
authors.affiliation: 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.
authors.forename: Pavel
authors.initials: P
authors.lastname: Anzenbacher
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czechia. Electronic address: moulin@email.cz.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Dvořák
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007527:Isoenzymes; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System
keywords: Chiral compounds; Cytochrome P450; Dihydropyridines; Human hepatocytes; Xenoreceptors