title: Hepatocytes are a rich source of novel aspirin-triggered 15-epi-lipoxin A(4).
abstract: Novel aspirin (ASA)-triggered 15-epi-lipoxins (ATL) comprise new potent bioactive eicosanoids that may contribute to the therapeutic effect of this drug. ATL biosynthesis is initiated by ASA acetylation of cyclooxygenase (COX)-2 and was originally identified during the interaction of leukocytes with either endothelial or epithelial cells. Here, we examined ATL biosynthesis in rat hepatocytes either alone or in coincubation with nonparenchymal liver cells (NPC) and in liver homogenates from ASA-treated rats. Rat hepatocytes and CC-1 cells, a rat hepatocyte cell line, displayed COX-1 but not COX-2 mRNA expression and predominantly produced thromboxane A(2) (TXA(2)) and 15-hydroxyeicosatetraenoic acid (15-HETE). In these cells, ASA shifted the arachidonic acid metabolism from TXA(2) to 15-HETE in a concentration-dependent manner. In contrast, neither indomethacin, ibuprofen, valeryl salicylate, nor nimesulide was able to trigger 15-HETE biosynthesis. SKF-525A, a cytochrome P-450 inhibitor, significantly reduced the effect of ASA on 15-HETE biosynthesis. Furthermore, phenobarbital, a potent inducer of cytochrome P-450 activity, further increased ASA-induced 15-HETE production. ASA treatment of hepatocyte-NPC coincubations resulted in the generation of significant amounts of ATL. In addition, in vivo experiments demonstrated augmented hepatic levels of 15-epi-lipoxin A(4) in ASA-treated rats. Taken together and considering that ASA is hydrolyzed on its first pass through the portal circulation, these data indicate that, during ASA's consumption, liver tissue generates biologically relevant amounts of ATL by COX-2-independent mechanisms.
authors.affiliation: DNA Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona 08036, Spain. gbw2@leicester.ac.uk
authors.forename: E
authors.initials: E
authors.lastname: Titos
authors.forename: N
authors.initials: N
authors.lastname: Chiang
authors.forename: C N
authors.initials: CN
authors.lastname: Serhan
authors.forename: M
authors.initials: M
authors.lastname: Romano
authors.forename: J
authors.initials: J
authors.lastname: Gaya
authors.forename: G
authors.initials: G
authors.lastname: Pueyo
authors.forename: J
authors.initials: J
authors.lastname: Clària
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics; D044045:Lipoxins; D008099:Liver / Q000737:chemistry* / Q000166:cytology / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins; D010634:Phenobarbital / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D006893:Hydroxyeicosatetraenoic Acids; D007527:Isoenzymes; D044045:Lipoxins; D008565:Membrane Proteins; D012333:RNA, Messenger; D013449:Sulfonamides; C040527:lipoxin A4; D013929:Thromboxane B2; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D001241:Aspirin; C012655:nimesulide; D007052:Ibuprofen; D007213:Indomethacin; D010634:Phenobarbital