Characterization of the Pharmacokinetics of Oral Selenium Compounds in Humans Before and Following Supplementation
Condition: Cancer
Study type: Observational

Summary: 
      The chemopreventive efficacy of Se was tested in a 10-year human intervention trial; total
      and lung cancer mortality, total cancer incidence, colorectal cancer and prostate cancer
      incidence decreased. This study is designed to compare, via stable isotope tracer studies the
      kinetics of inorganic and organic Se before and following two years of oral supplementation
      with L-selenomethionine, to measure forms of Se in the plasma (extracellular Se-dependent
      glutathione peroxidase [GSHPx], selenoprotein-P [SeP], albumin-bound Se [AlbSe] and
      nonprotein-bound low molecular weight [LMWSe] fractions), and to determine the effects of
      supplementation on the ecology of the hindgut microflora. The forms of Se were chosen to
      resemble the metabolism of the principal forms of Se in mixed American diets. Sodium
      selenite, an inorganic form, is metabolized by reduction to selenide which is then either
      used in the co-translational synthesis of SeCys in specific Se-containing proteins (e.g.,
      glutathione peroxidases, diodinases, selenoproteins P and W), or is converted to methylated
      excretion products; in this sense it resembles the food form selenocysteine (SeCys) which is
      metabolized to the selenide level. Selenomethionine (SeMet), an organic form, is a major form
      of Se in many foods, particularly those of plan origin. In addition to being metabolized to
      selenide, SeMet also enters the metabolic protein pool by competing with the
      sulfur-containing amino acid, methionine. A study is proposed to assess the impact of
      selenium (Se) supplementation on its metabolism in humans.

      A pilot study will be conducted to test recruitment strategies and sample collection,
      preparation and analysis and to assess the detectability of two stable isotopes given
      together. Four subjects will receive two 300 ug oral doses consisting of 150 ug of the stable
      isotope 76Se as selenite and 150 ug of the stable isotope 74Se as selenomethionine on study
      days one and twelve. Subjects will be followed for six weeks.

      In the first pharmacokinetics tracer study (PK1), twenty-eight subjects will receive the same
      two labeled stable isotope doses, and will be followed for 4 months. In addition, two
      subjects who have been self-supplementing with 200 ug of Se as selenized yeast for two years
      will take part in PK1 to assess the sensitivity over time of the tracer assay in supplemented
      subjects. PK1 will be followed by a 2-yr supplementation period, in which all 28 subjects
      will receive daily doses of 200 ug of L0SeMet; subjects = metabolism is expected to approach
      a new steady state reflective of long-term supplementation. A second 4-month pharmacokinetic
      tracer study (PK2) will then be conducted while subjects remain on Se-supplementation with an
      extension of six monthly blood samples. Extensive sampling of plasma, urine, and feces during
      PK1 and PK2 will permit both the refinement of existing baseline models for selenite and
      selenomethionine metabolism in humans and the investigation of changes in metabolism arising
      from Se-supplementation. The study is designed to detect a difference of 0.75 standard
      deviation units in pre-versus post-supplementation rate parameters, assuming a two-sided test
      with an alpha level of 0.05 and a power of 0.80.

      The non-absorbed portion of Se may favor portions of the normal colonic bacterial microflora
      that produce certain short-chain fatty acids that colon cells use for energy. To test this
      hypothesis, fecal specimens will be analyzed for short-chain fatty acids over the course of
      Se-supplementation. In addition, the sampling of buccal cell-Se and of toenail-Se on a
      quarterly basis over the course of the study and assay of thyroid hormone levels during the
      first year of the study will permit the investigation of possible changes in levels resulting
      from supplementation.
    

Detailed description: 
      The chemopreventive efficacy of Se was tested in a 10-year human intervention trial; total
      and lung cancer mortality, total cancer incidence, colorectal cancer and prostate cancer
      incidence decreased. This study is designed to compare, via stable isotope tracer studies the
      kinetics of inorganic and organic Se before and following two years of oral supplementation
      with L-selenomethionine, to measure forms of Se in the plasma (extracellular Se-dependent
      glutathione peroxidase [GSHPx], selenoprotein-P [SeP], albumin-bound Se [AlbSe] and
      nonprotein-bound low molecular weight [LMWSe] fractions), and to determine the effects of
      supplementation on the ecology of the hindgut microflora. The forms of Se were chosen to
      resemble the metabolism of the principal forms of Se in mixed American diets. Sodium
      selenite, an inorganic form, is metabolized by reduction to selenide which is then either
      used in the co-translational synthesis of SeCys in specific Se-containing proteins (e.g.,
      glutathione peroxidases, diodinases, selenoproteins P and W), or is converted to methylated
      excretion products; in this sense it resembles the food form selenocysteine (SeCys) which is
      metabolized to the selenide level. Selenomethionine (SeMet), an organic form, is a major form
      of Se in many foods, particularly those of plan origin. In addition to being metabolized to
      selenide, SeMet also enters the metabolic protein pool by competing with the
      sulfur-containing amino acid, methionine. A study is proposed to assess the impact of
      selenium (Se) supplementation on its metabolism in humans.

      A pilot study will be conducted to test recruitment strategies and sample collection,
      preparation and analysis and to assess the detectability of two stable isotopes given
      together. Four subjects will receive two 300 ug oral doses consisting of 150 ug of the stable
      isotope 76Se as selenite and 150 ug of the stable isotope 74Se as selenomethionine on study
      days one and twelve. Subjects will be followed for six weeks.

      In the first pharmacokinetics tracer study (PK1), twenty-eight subjects will receive the same
      two labeled stable isotope doses, and will be followed for 4 months. In addition, two
      subjects who have been self-supplementing with 200 ug of Se as selenized yeast for two years
      will take part in PK1 to assess the sensitivity over time of the tracer assay in supplemented
      subjects. PK1 will be followed by a 2-yr supplementation period, in which all 28 subjects
      will receive daily doses of 200 ug of L0SeMet; subjects = metabolism is expected to approach
      a new steady state reflective of long-term supplementation. A second 4-month pharmacokinetic
      tracer study (PK2) will then be conducted while subjects remain on Se-supplementation with an
      extension of six monthly blood samples. Extensive sampling of plasma, urine, and feces during
      PK1 and PK2 will permit both the refinement of existing baseline models for selenite and
      selenomethionine metabolism in humans and the investigation of changes in metabolism arising
      from Se-supplementation. The study is designed to detect a difference of 0.75 standard
      deviation units in pre-versus post-supplementation rate parameters, assuming a two-sided test
      with an alpha level of 0.05 and a power of 0.80.

      The non-absorbed portion of Se may favor portions of the normal colonic bacterial microflora
      that produce certain short-chain fatty acids that colon cells use for energy. To test this
      hypothesis, fecal specimens will be analyzed for short-chain fatty acids over the course of
      Se-supplementation. In addition, the sampling of buccal cell-Se and of toenail-Se on a
      quarterly basis over the course of the study and assay of thyroid hormone levels during the
      first year of the study will permit the investigation of possible changes in levels resulting
      from supplementation.
    

Keywords: Metabolism; Tracer Studies; Chemoprevention; Selenomethionine; Plasma Selenoproteins