Nuclear and Cytoplasmic Functions of Vitamin C.

Vitamin C (ascorbic acid) is a water-soluble antioxidant and a cofactor for a large number of enzymes. It is present in all tissues and especially abundant in corneal epithelium, stem cells, and neurons. Although similar to thiols in its ability to react with many reactive oxygen species (ROS), ascorbate is much better (>100× faster) than glutathione at scavenging of primary ROS (superoxide radical and singlet oxygen). Ascorbate appears to be especially important for elimination of O in the nucleus which contains little or no SOD activity. Cofactor functions of ascorbate involve the maintenance of activity of Fe(II)/2-oxoglutarate-dependent dioxygenases via reduction of Fe(III). The most prominent activity of ascorbate-dependent dioxygenases in the cytoplasm is hydroxylation of prolines in proteins involved in the formation of extracellular matrix and regulation of metabolism and hypoxia responses. In the nucleus, ascorbate is important for oxidative demethylation of 5-methylcytosine in DNA (by TET proteins) and removal of methyl groups from histone lysines (by JmjC demethylases). Differentiation and other cellular reprograming processes involving DNA demethylation are especially sensitive to ascorbate insufficiency. High doses of vitamin C alone or in combinations with drugs produced cancer-suppressive effects which involved redox, immune, and epigenetic mechanisms. Solutions to vitamin C deficiency in cultured cells are discussed to improve the physiological relevance of models. An abundance of vitamin C in rodents limits their ability to fully recapitulate human sensitivity to adverse health effects of malnutrition and xenobiotics, including neurotoxicity, lung injury, and intergenerational and other epigenetic effects.