PREDOMINANT EXPRESSION OF AN ARACHIDONATE EPOXYGENASE IN ISLETS OF LANGERHANS CELLS IN HUMAN AND RAT PANCREAS

Ou laboratory recently described a new human cytochrome P450 arachidon ic acid epoxygenase (CYP2J2) and the corresponding rat homolog (CYP2J3 ). Immunoblotting studies using a polyclonal antibody raised against r ecombinant human CYP2J2 confirmed CYP2J protein expression in human an d rat pancreatic tissues. Immunohistochemical staining of formalin-fix ed paraffin-embedded rat and human pancreas using the anti-CYP2J2 IgG and avidin-biotin-peroxidase detection revealed that CYP2J protein exp ression was highly localized to cells in the islets of Langerhans, wit h minimal staining in pancreatic exocrine cells. Colocalization studie s using antibodies to the glucagon, insulin, somatostatin, and pancrea tic polypeptide as markers for alpha-, beta-, delta-, and PP cells, re spectively, showed that CYP2J protein expression was abundantly presen t in all four cell types, but was highest in the glucagon-producing al pha-cells. Direct evidence for the epoxidation of arachidonic acid by pancreatic cytochrome P450 was provided by documenting, for the first time, the presence of epoxyeicosatrienoic acids in vivo in human and r at pancreas by gas chromatography/mass spectrometry. Importantly, the levels of immunoreactive CYP2J2 in different human pancreatic tissues were highly correlated with endogenous epoxyeicosatrienoic acid concen trations. We conclude that human and rat pancreas contain an arachidon ic acid epoxygenase belonging to the CYP2J subfamily that is highly lo calized to islet cells. These data together with previous work showing effects of epoxyeicosatrienoic acids in stimulating insulin and gluca gon secretion from isolated rat pancreatic islets support the hypothes is that epoxygenase products may be involved in stimulus-secretion cou pling in the pancreas.