Vitamin C (ascorbic acid) recommended dietary ingestion

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Specific Aims 1. Determination of renal thresholds for vitamin C in healthy men and women. 2. Determination of whether renal thresholds are disrupted in humans with common and rare diseases that involve kidneys. 2. Determine of whether single nucleotide polymorphisms in the renal ascorbate transporter change ascorbate pharmacokinetics in humans. 3. Validation of concentration-function approach to human vitamin C recommendations. Explanation Prior to 2000, recommended dietary allowances (RDAs) for vitamin C and other vitamins were based on preventing deficiency with a margin of safety. We proposed that new RDAs for vitamins, with vitamin C as a model, should be based on concentration-dependent vitamin functions. We termed this concentration-function approach in situ kinetics, with both molecular and clinical components. Some principles of in situ kinetics were adopted by the National Academy of Sciences as part of revised recommendations for all vitamin intakes. In situ kinetics is dependent on characterizing vitamin function in relation to vitamin concentration in human blood and tissues. For vitamin C, this approach depends on exploring vitamin C biochemistry and molecular biology; vitamin C physiology in humans; and vitamin C clinical pharmacokinetics. The overall hypothesis is that comprehensive and thorough characterization of vitamin physiology in healthy people will provide a key basis for RDAs, and will reveal vitamin pathophysiology in disease that can then be studied and corrected. Goals of clinical physiology and pharmacokinetics studies for vitamin C are to learn how its concentrations are achieved in humans as a function of dose, and to reveal the underlying mechanisms. To characterize these relationships, clinical studies were undertaken at the NIH Clinical Center. Healthy young men and women were hospitalized for 5-7 months, and extensive pharmacokinetics data were collected. Many of these data have been published. Based on portions of these clinical data, RDAs for vitamin C in the United States and Canada were revised upward in 2000 by the National Academy of Sciences, and were also increased in Germany, Austria, Denmark, France, Japan, and China. Analyses of unpublished data are on-going. Based on these pharmacokinetics data, we observed that orally ingested vitamin C over an 80- fold dose range resulted in tightly controlled plasma and tissue concentrations. Tight control appeared to be mediated by three coordinated physiologic processes: intestinal absorption; tissue transport/accumulation; and renal filtration/reabsorption. Utilization is a fourth contributor to tight control. Renal filtration and reabsorption appeared to have a central role in tight control. Therefore, we developed and utilized new techniques to allow us to accurately determine the renal threshold for vitamin C in health and disease. Samples were collected from 20 healthy subjects on a controlled diet. Data analyzed included thousands of plasma and urine data points obtained from 36-hour bioavailability experiments, conducted at steady-state at each of 7 different vitamin C doses in these 20 healthy subjects. Samples were analyzed by coulometric electrochemical detection coupled to HPLC. This technique eliminates measurement uncertainties for vitamin C, including issues related to sensitivity, stability in samples, specificity, and substance interferences. Analyses of these data allowed us to determine sex-specific renal thresholds, the first of their kind, for healthy men and women (Ebenuwa et al. 2022 Amer J. Clin Nutr). Based on these findings, we then developed a simpler sample collection strategy, a one-hour timed urine collection coupled to a plasma collection after an overnight fast. This technique allowed us to collect samples from healthy subjects; subjects with diabetes; men with a rare X-linked genetic disease that involves renal function (Fabry disease); and women who were receiving antiretroviral therapy for HIV. We found that when plasma vitamin C concentrations were below sex-specific renal thresholds, there was abnormal urinary vitamin C loss a renal leak in people with diabetes, Fabry disease, and HIV who were receiving therapy. We analyzed renal leak in these cohorts, plus control subjects. Across the four cohorts, a higher renal leak prevalence was associated with lower mean plasma vitamin C concentrations (p<0.001) and a higher prevalence of vitamin C deficiency (p<0.001). Compared to healthy people, these data provide novel evidence that vitamin C physiology is disrupted in people with both rare and common diseases. As a consequence, vitamin C needs in people with these diseases may be higher than those of healthy people. Our hypothesis is that rigorous characterization of vitamin physiology in healthy people is foundational for RDAs and for predicting vitamin pathophysiology in disease, with potential for disease prevention and/or clinical benefit by correcting unanticipated vitamin deficiency states. Our approaches, using clinical physiology and intensive pharmacokinetics studies to determine a vitamin recommendation, are the first of their kind for any vitamin. The overall concept has been expanded with vitamin E (alpha-tocopherol), using deuterated tocopherols and described in a separate report. Only with this approach could unanticipated discoveries occur, including those for cancer therapeutics and hepato-steatosis, also described in separate reports.