Vitamin C activation of the biosynthesis of epoxyeicosatrienoic acids


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.

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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.

Conflicts of Interest

The authors declare no conflicts of interest.


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