title: Murine atrial HL-1 cell line is a reliable model to study drug metabolizing enzymes in the heart.
abstract: HL-1 cells are currently the only cells that spontaneously contract while maintaining a differentiated cardiac phenotype. Thus, our objective was to examine murine HL-1 cells as a new in vitro model to study drug metabolizing enzymes. We examined the expression of cytochrome P450s (Cyps), phase II enzymes, and nuclear receptors and compared their levels to mice hearts. Our results demonstrated that except for Cyp4a12 and Cyp4a14 all Cyps, phase II enzymes: glutathione-S-transferases (Gsts), heme oxygenase-1 (HO-1), and NAD(P)H: quinone oxidoreductase (Nqo1), nuclear receptors: aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and peroxisome proliferator activated receptor (PPAR-alpha) were all constitutively expressed in HL-1 cells. Cyp2b19, Cyp2c29, Cyp2c38, Cyp2c40, and Cyp4f16 mRNA levels were higher in HL-1 cells compared to mice hearts. Cyp2b9, Cyp2c44, Cyp2j9, Cyp2j11, Cyp2j13, Cyp4f13, Cyp4f15 mRNA levels were expressed to the same extent to that of mice hearts. Cyp1a1, Cyp1a2, Cyp1b1, Cyp2b10, Cyp2d10, Cyp2d22, Cyp2e1, Cyp2j5, Cyp2j6, Cyp3a11, Cyp4a10, and Cyp4f18 mRNA levels were lower in HL-1 cells compared to mice hearts. Moreover, 3-methylcholanthrene induced Cyp1a1 while fenofibrate induced Cyp2j9 and Cyp4f13 mRNA levels in HL-1 cells. Examining the metabolism of arachidonic acid (AA) by HL-1 cells, our results demonstrated that HL-1 cells metabolize AA to epoxyeicosatrienoic acids, dihydroxyeicosatrienoic acids, and 20-hydroxyeicosatetraenoic acids. In conclusion, HL-1 cells provide a valuable in vitro model to study the role of Cyps and their associated AA metabolites in addition to phase II enzymes in cardiovascular disease states.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Osama H
authors.initials: OH
authors.lastname: Elshenawy
authors.forename: Anwar
authors.initials: A
authors.lastname: Anwar-Mohamed
authors.forename: Ghada
authors.initials: G
authors.lastname: Abdelhamid
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002460:Cell Line; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004798:Enzymes / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006325:Heart Atria / Q000166:cytology / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: C000717353:Cyp2j6 protein, mouse; D004798:Enzymes; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2