Author(s)

Houli Jiang, Fiona E. Harrison, Kavita Jain, Samantha Benjamin, James M. May, Joan P. Graves, Darryl C. Zeldin, John R. Falck, Bruce D. Hammock, John C. McGiff

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Entomology and Cancer Center, University of California, Davis, California, USA.
NIH/NIEHS, Research Triangle Park, North Carolina, USA.

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 of cis- and trans-EETs and the regulation of EET levels in rat isolated perfused kidneys and in vivo. VitC biphasically stimulated rat kidney microsomal cis- and trans-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 preferred trans- over cis-EET formation from arachidonic acid and was associated with the cleavage of LOOHs, which indicated a CYP peroxy-genase 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, mostly trans-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 formation in vivo in 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.

Vitamin C; Epoxyeicosatrienoic Acids; Cytochrome P450; Lipid Hydroperoxides; Peroxygenase

Jiang, H. , Harrison, F. , Jain, K. , Benjamin, S. , May, J. , Graves, J. , Zeldin, D. , Falck, J. , Hammock, B. and McGiff, J. (2012) Vitamin C activation of the biosynthesis of epoxyeicosatrienoic acids. Advances in Bioscience and Biotechnology, 3, 204-218. doi: 10.4236/abb.2012.33029.