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Predominant Expression of an Arachidonate Epoxygenase in Islets of Langerhans Cells in Human and Rat Pancreas

Laboratories of Pulmonary Pathobiology (D.C.Z., J.E.B., C.R.M., S.W.), Experimental Pathology (J.F.), and Molecular Biophysics (K.B.T., C.P.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; the Department of Medicine, University of North Carolina (J.E.B.), Chapel Hill, North Carolina 27599; and the Department of Pathology, Duke University Medical Center (C.S.), Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Darryl C. Zeldin, Laboratory of Pulmonary Pathobiology, NIH, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709. E-mail: ZELDIN{at}NIEHS.NIH.GOV

Our laboratory recently described a new human cytochrome P450 arachidonic acid epoxygenase (CYP2J2) and the corresponding rat homolog (CYP2J3). Immunoblotting studies using a polyclonal antibody raised against recombinant human CYP2J2 confirmed CYP2J protein expression in human and rat pancreatic tissues. Immunohistochemical staining of formalin-fixed paraffin-embedded rat and human pancreas using the anti-CYP2J2 IgG and avidin-biotin-peroxidase detection revealed that CYP2J protein expression was highly localized to cells in the islets of Langerhans, with minimal staining in pancreatic exocrine cells. Colocalization studies using antibodies to the glucagon, insulin, somatostatin, and pancreatic polypeptide as markers for -, ß-, -, and PP cells, respectively, showed that CYP2J protein expression was abundantly present in all four cell types, but was highest in the glucagon-producing -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 rat pancreas by gas chromatography/mass spectrometry. Importantly, the levels of immunoreactive CYP2J2 in different human pancreatic tissues were highly correlated with endogenous epoxyeicosatrienoic acid concentrations. We conclude that human and rat pancreas contain an arachidonic acid epoxygenase belonging to the CYP2J subfamily that is highly localized to islet cells. These data together with previous work showing effects of epoxyeicosatrienoic acids in stimulating insulin and glucagon secretion from isolated rat pancreatic islets support the hypothesis that epoxygenase products may be involved in stimulus-secretion coupling in the pancreas.

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