title: Vitamin C activation of the biosynthesis of epoxyeicosatrienoic acids.
abstract: The cardiovascular effects of vitamin C (VitC) could be mediated by epoxyeicosatrienoic acids (EETs). We aimed to study the mechanism of VitC-dependent microsomal formation ofcis- andtrans-EETs and the regulation of EET levels in rat isolated perfused kidneys andin vivo. VitC biphasically stimulated rat kidney microsomalcis- andtrans-EET formation in a ratio of 1:2, involving the participation of lipid hydroperoxides (LOOHs), Fe2+, and cytochrome P450 (CYP). Levels of LOOHs correlated with microsomal EET production. LOOH stimulation of CYP isoforms resulted in preferredtrans-overcis-EET formation from arachidonic acid and was associated with the cleavage of LOOHs, which indicated a CYP peroxygenase activity. EETs contributed to VitC-induced vasodilator responses in rat isolated perfused kidneys. VitC (1 mg/ml) given in the drinking water for 9 days doubled rat urinary EET excretion, increased plasma levels of EETs, mostlytrans-EETs, by 40%, and reduced plasma levels of 20-hydroxyeicosatetraenoic acid. Depletion of VitC in brain cortex and kidney tissues by more than 20- and 50-fold, respectively, in gulonolactone oxidase-knockout mice was associated with mild increases in tissue EETs. These data suggest that LOOHs are a determinant factor for EET formationin vivoin which VitC exerts a key regulatory effect. VitC-activated CYP peroxygenase activity may represent a CYP interaction with lipoxygenases and cyclooxygenases to mediate the cardiovascular effects of VitC via formation of EETs.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
authors.forename: Houli
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Harrison
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Jain
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Benjamin
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: May
authors.affiliation: NIH/NIEHS, Research Triangle Park, North Carolina, USA.
authors.forename: Joan P
authors.initials: JP
authors.lastname: Graves
authors.affiliation: NIH/NIEHS, Research Triangle Park, North Carolina, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Entomology and Cancer Center, University of California, Davis, California, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: McGiff
keywords: Cytochrome P450; Epoxyeicosatrienoic Acids; Lipid Hydroperoxides; Peroxygenase; Vitamin C