Hepatocytes are a rich source of novel aspirin-triggered 15-epi-lipoxin A4

Novel aspirin (ASA)-triggered 15-epi-lipoxins (ATL) comprise newpotent 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 theinteraction of leukocytes with either endothelial or epithelial cells.Here, we examined ATL biosynthesis in rat hepatocytes either alone orin coincubation with nonparenchymal liver cells (NPC) and in liverhomogenates from ASA-treated rats. Rat hepatocytes and CC-1 cells, arat hepatocyte cell line, displayed COX-1 but not COX-2 mRNA expressionand predominantly produced thromboxane A₂(TXA₂) and15-hydroxyeicosatetraenoic acid (15-HETE). In these cells, ASA shiftedthe arachidonic acid metabolism fromTXA₂ to 15-HETE in aconcentration-dependent manner. In contrast, neither indomethacin,ibuprofen, valeryl salicylate, nor nimesulide was able to trigger15-HETE biosynthesis. SKF-525A, a cytochromeP-450 inhibitor, significantly reducedthe effect of ASA on 15-HETE biosynthesis. Furthermore, phenobarbital,a potent inducer of cytochrome P-450activity, further increased ASA-induced 15-HETE production. ASAtreatment of hepatocyte-NPC coincubations resulted in the generation ofsignificant amounts of ATL. In addition, in vivo experimentsdemonstrated augmented hepatic levels of 15-epi-lipoxin A₄ in ASA-treated rats. Takentogether and considering that ASA is hydrolyzed on its first passthrough the portal circulation, these data indicate that, during ASA'sconsumption, liver tissue generates biologically relevant amounts ofATL by COX-2-independent mechanisms.