Dr. Mark A. Levine, MD is a Senior Investigator of the National Institute of Diabetes and Digestive and Kidney Diseases’ Molecular and Clinical Nutrition Section in Digestive Disease Branch.
Dr. Levine’s laboratory conducts basic, translational, and clinical research which aims to determine optimal nutrition in health, disease, and treatment. His research focuses on vitamin C (ascorbic acid) to determine a functional basis for nutrient recommendations.
Ascorbic Acid Physiology and Pharmacokinetics: Recommended Intake; Cancer Treatment; and Preventing Diabetes Complications
For many vitamins, recommended intakes are based on preventing deficiency with a safety margin. Instead we proposed that recommended vitamin intake could be based on vitamin function in vivo. The overarching hypothesis is determination of vitamin functions in people in relation to vitamin concentrations, or kinetics in situ. Approaches were to conduct intensive physiology and pharmacokinetics studies in healthy people. We chose vitamin C (ascorbic acid, ascorbate) as a model vitamin. The initial step was characterization of kinetics in situ for a vitamin C-dependent function, the first such description for any vitamin. Because these kinetics studies utilized animal tissues, next steps were to characterize kinetics in humans. Essential prerequisites were to learn vitamin C concentrations in humans in relation to dose. To do so, pharmacokinetics studies of vitamin C were conducted in healthy humans, using a depletion-repletion design. Healthy people under age 30 were studied as inpatients at the National Institutes of Health Clinical Center for approximately 6 months each. Subjects consumed a vitamin C-deficient diet that was corrected for other vitamin deficiencies, and received vitamin C doses from 30 to 2500 mg. Data indicated that vitamin C concentrations in plasma and tissues were tightly controlled, by four mechanisms: intestinal absorption; tissue transport; renal reabsorption/excretion; and utilization. Recommended vitamin C intakes in many countries utilize these data. Bioavailability studies to characterize intestinal absorption showed that intravenous administration by-passed tight control mechanisms, until homeostasis was restored by renal excretion. Depending on dose, intravenous administration produced ascorbate plasma concentrations nearly 1000 times higher than those possible with oral dosing. Pharmacologic ascorbate concentrations produced only by intravenous administration killed cancer cells but not normal cells in vitro and reduced tumor growth in animals, without toxicity. The mechanism was dependent on formation of extracellular hydrogen peroxide, confirmed by measuring hydrogen peroxide in vivo in extracellular fluid. Once extracellular peroxide formed, multiple downstream targets caused death of cancer but not normal cells. Pharmacologic ascorbate administration in people appears safe with minimal adverse events, and phase I and early phase II treatment trials using pharmacologic ascorbate have promising results. Because transport was essential for tight control of vitamin C concentrations, we investigated whether transport of the related compound dehydroascorbic acid, or oxidized vitamin C, had any clinical relevance. Under physiologic conditions, only dehydroascorbic acid was transported on glucose transporters into mouse and human red blood cells, with immediate intracellular reduction to ascorbate. There was an inverse relationship between red blood cell deformability, measured by osmotic fragility, and ascorbate concentrations. In vivo, plasma glucose concentrations in normal and diabetic mice and humans were inversely related to red cell ascorbate concentrations, as was osmotic fragility. Diabetes lowered red blood cell ascorbate and increased rigidity, a candidate to drive microvascular angiopathy. Thus, diabetes might produce an ascorbate deficiency in red cells: famine from feast. In this case, red cell rigidity may be reversible by correcting an unexpected ascorbate deficiency. Ascorbate in the red blood cell in diabetes is a new example of how disease can modify vitamin kinetics in situ. The concentration-function hypothesis plus physiology and pharmacokinetics approaches represent a paradigm to learn ideal vitamin intakes for many vitamins, and may reveal unanticipated roles of vitamins in disease prevention and treatment.
- Levine M, Violet PC. Data Triumph at C. Cancer Cell. 2017;31(4):467-469.
- Tu H, Li H, Wang Y, Niyyati M, Wang Y, Leshin J, Levine M. Low Red Blood Cell Vitamin C Concentrations Induce Red Blood Cell Fragility: A Link to Diabetes Via Glucose, Glucose Transporters, and Dehydroascorbic Acid. EBioMedicine. 2015;2(11):1735-50.
- Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014;6(222):222ra18.