Vitamin E Pharmacokinetics And Biomarkers In Normal And Obese Women

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Explanation Although vitamin E (alpha-tocopherol) is essential for humans, clinical deficiency is extremely rare, and a specific alpha-tocopherol-dependent pathway in humans has not been described. For these reasons, there is difficulty in establishing human dietary requirements and intake recommendations. Both are currently based on vitamin E intakes in men that prevented hydrogen-peroxide induced hemolysis of red blood cells in vitro. Our overarching hypothesis is that vitamin recommendations can be based on concentration-function relationships, using approaches of in vivo physiology and pharmacokinetics. For alpha-tocopherol, approaches can utilize stable isotopes of alpha-tocopherol administered orally and /or intravenously. Using stable isotopes, our specific goals were to determine bioavailability of alpha-tocopherol in relation to ingested fat, and longer-term turnover kinetics. Because alpha-tocopherol is a fat-soluble vitamin, we determined true bioavailability, or fractional absorption, with 40% fat or no fat upon ingestion of deuterated vitamin. True bioavailability/fractional absorption was determined in healthy women with simultaneously administered deuterated oral alpha-tocopherol (alpha-tocopherol with 3 deuterium molecules, d3-alpha-tocopherol) and intravenously administered deuterated alpha-tocopherol (alpha-tocopherol with 6 deuterium molecules, d6-alpha-tocopherol). We found that, over 72 hours, alpha-tocopherol fractional absorption quantitatively was not limited by fat. However, in the absence of fat, alpha-tocopherol availability to the general circulation was incomplete until fat was ingested subsequently. Our studies with simultaneous administration of deuterated oral alpha-tocopherol (alpha-tocopherol with 3 deuterium molecules, d3-alpha-tocopherol) and intravenously administered deuterated alpha-tocopherol (alpha-tocopherol with 6 deuterium molecules, d6-alpha-tocopherol) showed that the liver has a key role in normal physiology of vitamin E and its movement into the circulation on lipoproteins. Since alpha-tocopherol is fat soluble, we predicted that abnormal fat in the liver (hepato-steatosis) would disrupt normal physiology in humans, by acting to sequester the vitamin. These predictions were tested and confirmed in women with hepato-steatosis but without hepatitis. Our studies are the first studies for any vitamin to use dual heavy labeled (deuterated) oral and intravenous preparations to study vitamin physiology and pharmacokinetics in humans. The data are the first to provide true bioavailability information for alpha-tocopherol; reveal unexpected pathophysiology of alpha-tocopherol in hepato-steatosis; offer an unexpected and new means to prevent hepato-steatosis from advancing to steatohepatitis (non-alcoholic steato-hepatitis, NASH); and are a foundation for a new determination of vitamin E requirements in healthy humans. These studies validate a physiology/pharmacokinetics approach to vitamin recommendations, and provide a new path to determine optimal vitamin ingestion for many vitamins. This work will advance in humans when fresh deuterated oral and intravenous alpha-tocopherol preparations are again available. Based on the observations from our clinical studies, bedside-to-bench experiments to investigate alpha-tocopherol physiology and pathophysiology are underway.