Handbook of Vitamin C Research

Human Specific Vitamin C Metabolism… 77(1) Human Specific VC Metabolism and TransportHuman VC metabolism is essential to prevent xenobiotic damage [1] and oxidative stress[9] through oxidation of AsA to monodehydroascorbate radicals and DAsA [1, 23]. Oxidativeimbalance is an important contributor to aging and degenerative diseases of all animals [14].However, human VC metabolism is markedly different from that of VC autotrophs [1, 22].To overcome VC auxotrophy, rapid reducing and transporting through GLUT1 for recyclingDAsA [16, 26, 69], high uric acid concentrations [24, 29] and low dehydroascorbataseactivity [3, 46] developed in the human body. DAsA enters mitochondria via GLUT1 andprotects mitochondria from oxidative injury [43]. Since mitochondria contribute significantlyto intracellular ROS, protection of the mitochondrial genome and membrane may havepharmacological implications against a variety of ROS-mediated disorders [43].(2) Molecular Genetics of VC MetabolismStudies on oxidoreduction of glutathione [48] and serum albumin [49], explained therapid DAsA reduction to protect DAsA hydrolysis in slightly alkaline cytosol and serum (pH7.4). Thus, genetic polymorphisms in xenobiotic enzymes affecting glutathione and otheroxidative stress-related substrates affect VC metabolism.In the VC loading experiments on subjects with polymorphisms in glutathione Stransferase 1 (GSTP1), total VC excretion (46.7 ± 18.1 mg) by AA homozygotes of GSTP1was greater (p < 0.0069) than that (28.2 ± 14.0 mg) by GA heterozygotes, with no differencesseen in GFR (90 ml/min) [4, 5]. In the same subjects, blood total VC levels were alsosignificantly different (p < 0.0036) between the homozygotes and heterozygotes [4, 5]. Otherpolymorphisms in xenobiotic enzymes may also affect VC metabolism.The pleiotropic functions of dehydroascorbatase [3, 46, 80], antixenobiotic paraoxanase[56], anti-aging SMP30 [51, 52], regucalcin [57] and lactonase [53], attracted numerousresearchers because it is the most abundant liver protein, accounting for 1% of total protein[53], but it decreases with age [55]. Recent studies by X-ray crystallography [54] and aminoacid sequencing (99 amino acids in mammals) [51, 52] revealed that the Ca-coordinatingamino acid residues (E17, N103, N155 and D204) are conserved among mammals, and thereare human-specific residues (K83, N95, V232 and N253). The VC auxotrophy iscompensated by deletion of uricase, mutation of dehydroascorbatase [3, 51, 52] and manyother changes in the gene expression [84]. The human VC auxotrophy is now restored byintroduction of active GLO gene into a human cell line [85].(3) VC Loading ExperimentsSince the classical loading experiments of AsA and DAsA by Linkswiler [61] forAmericans, and by Tsujimura [70] for Japanese, nutritional values of AsA and DAsA havebeen estimated to be equal in humans [4, 5, 8]. However, the effects of DAsA are only 10%of those of AsA in GLO-knockout rat [71]. The Pauling‘s recommendation to ingest 2.3g or