Beta-carotene is found in the diets of virtually all humans around the world. Its best known functions are to provide vitamin A and to treat erythropoietic protoporphria. While a large body of evidence indicates that dietary beta-carotene reduces the risk of cancer an chronic disease, several large chernoprevention trials found that pharmacologic supplements of beta-carotene may cause cancer in certain high-risk subpopulations. Despite its clinical significance the metabolism of beta-carotene and its ability to deliver bioactive retinoids to tissues and organs is poorly understood. The long-range goal is to define the behavior of human beta-carotene metabolism in terms of hereditary and environmental factors that can affect it. The immediate objective is to determine the bioavailability and vitamin A value of ingested beta-carotene using Accelerator Mass Spectrometry detection in 15 male and 15 female subjects. The experimental design is longitudinal test-retest format that will establish the prevalence and stability of metabolic phenotypes to beta-carotene. The central hypothesis is that a discrete and significant percentage of the population utilizes beta-carotene very inefficiently. These individual are identified by a low plasma response to ingested beta-carotene that can result from low intestinal absorption and bioconversion of beta-carotene to vitamin A following a beta-carotene oral dose. Identification of the phenomenon as stable characteristic (metabolic phenotype would suggest a genetic basis of it. The proposal is unique in that these investigators can determine mass balance as well as follow major and minor vitamin A metabolites of radiolabeled beta-carotene at attomole levels of sensitivity with excellent measurement precision. There are four specific aims. (1) Determine the bioavailability of a 1 mg oral dose of beta-[14C]carotene (100 nanoCi) in 15 male and 15 female subjects. Bioavailability is determined by mass balance for 10 days. Urinary loss is determined from complete 10-d urine collections. (2) Determine the vitamin A value of beta-carotene by quantitative analysis of postprandial retinyl esters, retinoic acids, and retinol in blood. (3) Assess the long-term kinetics of beta-carotene, retinol, retinoic acids and novel metabolites by HPLC fractionation of plasma with AMS analysis of label out to 40 days. (4) Repeat aims 1,2,and 3 on day 75 (retest) to assess stability of metabolic phenotype and variance of the individual response. The expectations are that, at the conclusion of the proposed period of support, we will have determined important parameters of beta-carotene metabolism that include its vitamin A value, bioavailability, and established or rejected the concept of the discrete metabolic phenotype. These studies can serve as a basis for future investigations into the influence of environmental, genetic, and drug/nutrient interactions on the behavior of beta-carotene metabolism.
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