Based on extensive pharmacokinetics data from this laboratory, we have learned that Vitamin C concentrations are tightly controlled in healthy humans as a function of vitamin C dose. Three physiologic processes appear to be responsible: intestinal absorption, tissue transport, and renal filtration/reabsorption. In particular, our pharmacokinetics data indicate that the renal threshold of excretion plays a key role in the observed tight control of vitamin C concentrations in plasma and tissues. We hypothesized that Slc23a1, the vitamin C epithelial transporter expressed in kidney, is responsible for tight control. To test this we created a mouse null for the Slc23a1 gene. Inbred C57bL/6J wild type, Slc23a1+/- and Slc23a1-/- mice were generated on a Balb/c background. After weaning, growth rates of wild type, Slc23a1+/- and Slc23a1-/- mice were indistinguishable. Urine vitamin C fractional excretion was 7-10 fold higher in Slc23a1-/- mice compared to wildtype littermates. Corresponding plasma ascorbic acid concentrations in slc23a1-/- mice were 50-70% lower than in wild type littermates. In slc23a1-/- mice, neuronal tissue ascorbate concentrations levels were unaffected by the depressed plasma ascorbate levels, whereas all other tissues trended downwards. These data show that Slc23a1 is responsible for tight control of vitamin C, via regulation of renal threshold of excretion. The asymmetric response of tissues to decreased plasma vitamin C may represent redistribution of vitamin C to protect brain function. Active investigation is underway to describe the consequences of the vitamin C renal leak in these animals. Humans with Slc23a1 single nucleotide polymorphisms that decrease activity of the renal vitamin C transporter might also have altered vitamin C pharmacokinetics due to a renal leak, and therefore require additional vitamin C intake. These findings have unique implications for recommended dietary allowances, because they may need to account for individual genetic differences. Vitamin C is accumulated in human lymphocytes and monocytes, but its function is unknown. We hypothesized that vitamin C might regulate gene transcription in these cells. To investigate, we studied lymphocyte-enriched and monocyte-enriched cell populations isolated from whole blood by in vivo apheresis from 11 healthy women who were 19-27 years old. Cells were isolated from the same women at steady state at each of the following daily vitamin C doses: 30mg;60 mg;100 mg;and 1000 or 2500 mg. Comparisons to determine significant changes in gene expression were performed using mRNA from the same subjects at different doses, with RNA obtained at 30 mg as baseline. Gene expression was analyzed using Affymatrix arrays, statistical and pathway software (GeneSpring, Partek, GeneGo), and confirmed by quantitative real time PCR. The data showed that in monocyte enriched populations, higher Vitamin C doses significantly increased expression of multiple components of three similar pathways: CD28 signaling;ICOS-ICOSL signaling;and T cell receptor signaling. Also, in monocyte enriched populations, the EGF signaling pathway was significantly increased with increasing vitamin C doses. In lymphocytes, fewer pathways were affected compared to monocytes. These analyses reveal novel functions of vitamin C on gene transcription in circulating cells in human plasma. These are the first data describing changes in gene expression as a function of varying nutrient concentrations in the same human subjects, for any nutrient.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Eck, Peter K; Corpe, Christopher; Levine, Mark A (2017) Temporo-spacial microanatomical distribution of the murine sodium-dependent ascorbic acid transporters Slc23a1 and Slc23a2 in the kidney throughout development. Biochem Cell Biol 95:421-427
Tu, Hongbin; Wang, Yu; Li, Hongyan et al. (2017) Chemical Transport Knockout for Oxidized Vitamin C, Dehydroascorbic Acid, Reveals Its Functions in vivo. EBioMedicine 23:125-135
Renoux, CĂ©line; Parrow, Nermi; Faes, Camille et al. (2016) Importance of methodological standardization for the ektacytometric measures of red blood cell deformability in sickle cell anemia. Clin Hemorheol Microcirc 62:173-9
Padayatty, S J; Levine, M (2016) Vitamin C: the known and the unknown and Goldilocks. Oral Dis 22:463-93
Corpe, Christopher P; Eck, Peter; Wang, Jin et al. (2013) Intestinal dehydroascorbic acid (DHA) transport mediated by the facilitative sugar transporters, GLUT2 and GLUT8. J Biol Chem 288:9092-101
Eck, Peter; Kwon, Oran; Chen, Shenglin et al. (2013) The human sodium-dependent ascorbic acid transporters SLC23A1 and SLC23A2 do not mediate ascorbic acid release in the proximal renal epithelial cell. Physiol Rep 1:e00136
Li, Hongyan; Tu, Hongbin; Wang, Yaohui et al. (2012) Vitamin C in mouse and human red blood cells: an HPLC assay. Anal Biochem 426:109-17
Corpe, Christopher P; Tu, Hongbin; Eck, Peter et al. (2010) Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. J Clin Invest 120:1069-83
Eisner, Christoph; Faulhaber-Walter, Robert; Wang, Yaohui et al. (2010) Major contribution of tubular secretion to creatinine clearance in mice. Kidney Int 77:519-26
Erichsen, Hans Christian; Peters, Ulrike; Eck, Peter et al. (2008) Genetic variation in sodium-dependent vitamin C transporters SLC23A1 and SLC23A2 and risk of advanced colorectal adenoma. Nutr Cancer 60:652-9

Showing the most recent 10 out of 11 publications