Chapter one
A “C Odyssey”
Recommended Dietary Allowances and Optimal Health: Paradigm and Promise of Vitamin C
Mark Levine, Pierre-Christian Violet, Ifechukwude C. Ebenuwa, Hongbin Tu, and Yaohui Wang
Contents
Introduction: Recommended Dietary Allowances and Their Limitations
Concentration-Function Hypothesis: Physiology/Pharmacokinetic Approaches
Vitamin C as a Model Vitamin
Vitamin C Physiology and Pharmacokinetics in Healthy Humans: Tight Control and Underlying Mechanisms
Bioavailability and Unexpected Consequences
Tissue Transport and Unexpected Consequences
Renal Reabsorption
Utilization
Paradigm and Promise
Abbreviations
Acknowledgments
References
Introduction: Recommended Dietary Allowances and their Limitations
The nutritional biochemist Alfred E. Harper was a member of the Food and Nutrition Board (FNB) of the National Research Council/National Academy of Sciences for many years, and chair of the Food and Nutrition Board from 1978 to 1982. In a number of articles, he described the original intent of Recommended Dietary Allowances (RDAs) in the United States, briefly summarized as follows [1–3]. In 1940, to guide the U.S. government concerning national defense, a Committee on Food and Nutrition was established under the National Research Council, U.S. National Academy of Sciences, to advise the government on problems concerned with national defense. In 1941, the committee name was changed to the FNB. The allowances for specific nutrients from the FNB were intended to serve as a guide for planning adequate nutrition for U.S. civilians. Specifically, there was no intent to have RDAs as guides to perfect health, nor were they designed to attain ideal intakes. The RDA was stated to be not just “minimal sufficient to protect against actual deficiency disease” but sufficient “to ensure good nutrition and protection of all body tissues,” and in the 1953 edition they are stated to be “nutrient allowances suitable for the maintenance of good nutrition in essentially the total population.” The scientific bases for many RDAs were prevention of deficiency with a margin of safety, often determined from depletion-repletion studies or balance experiments. As Harper wrote, “The RDA has been adopted and adapted by various organizations for many purposes, but they were devised for the planning and procurement of food supplies that would be nutritionally adequate for population groups. Therefore, any assessment of the adequacy, accuracy, and reliability of the RDA will be meaningful only if it is done in relation to their use for this primary purpose. To base such an assessment on their adequacy for other purposes would be like judging the adequacy of the design of the family car for use as a snowplow” [3].
As nutritional science has grown, and policy needs have changed, limitations of RDAs were recognized. Beginning in the 1990s, the FNB expanded nutritional intake concepts in the form of dietary reference intakes, commonly known as DRIs [4–6]. Unfortunately, because of data limitations, scientific bases for many dietary reference intakes remain as prevention of deficiency with a margin of safety, because these are the only data available.
To paraphrase Alfred E. Harper, when there is heavy snow, you need a snowplow. To achieve a nutrition goal, we have to be thoughtful in defining the nutrition problem that we are addressing, and if necessary, to think outside the box to solve the problem. Prevention of deficiency with a safety margin is not the only means to determine nutrient intake, nor, from a clinical vantage point, is it the preferred one. If there truly were a means to realize goals of ideal nutrient intake, there would be unprecedented possibilities to optimize health, prevent disease, and even treat disease. But specific methods and measures are essential to realize such lofty possibilities. Such specifics have taken decades to formulate, evolve, and solidify. What is so simple in concept has been so difficult to bring to fruition.
Concentration-Function Hypothesis: Physiology/Pharmacokinetic Approaches
Fundamental biochemical kinetics concepts can be the foundation for nutrient recommendations. Such concepts derive from work of Tatum and Beedle [7], David Perla and Jesse Marmorston [8], Roger Williams [9,10], and, perhaps surprisingly and independent of his later involvement with ascorbic acid in colds and cancer, Linus Pauling [11–13]. With these biochemical and experimental supports, a new hypothesis was proposed: bases of vitamin recommendations could be concentration-function relationships, or kinetics relationships, in cells, tissues, animals, and healthy humans [14–17]. Approaches were to conduct physiology and pharmacokinetic studies in healthy humans. Stated in another way, the overarching concept was that kinetics in situ would underlie vitamin recommendations in healthy people. Physiology and pharmacokinetic studies would provide essential data for the x-axis, those concentrations found in vivo, preferably in humans. With concentration data describing an x-axis, function, or the y-axis, could follow in relation to concentrations in vivo [18].
Vitamin C as a Model Vitamin
For such work to proceed, a vitamin was selected arbitrarily: ascorbic acid. Initial efforts were focused on assay development and proof of concept. Accurate assay of ascorbic acid was an essential prerequisite, a foundation on which everything else was based. Since its discovery and isolation, ascorbic acid measurements had many uncertainties, due to limitations of sensitivity, specificity, stability, and confounding substance interferences [19]. The emergence of high-performance liquid chromatography (HPLC) techniques coupled to electrochemical detection provided a path forward [20]. A new assay was developed that addressed and solved these issues, using HPLC specifically coupled to coulometric (flow-through) electrochemical detection [21,22]. With this assay, the concept was tested and verified that kinetics relationships could be determined in situ for ascorbic acid. The experimental system was ascorbic acid–dependent norepinephrine biosynthesis in chromaffin granules, the secretory vesicles of adrenal medulla, isolated from bovine (cow) adrenal glands [23–25]. Norepinephrine synth...
