2009-12-28

evangelizing non-toxic selenium

temp anti-cancer selenium-cysteine compounds
Se-methylselenocysteine is the most valuable form of selenium
[11.3: . garlic grown in a selenium-rich medium can produce Se-methylselenocysteine;
which has been demonstrated in animal carcinogenesis bioassays
to be a potent cancer chemopreventive agent . ]

[2012.2.18: updated table of contents:]


  • introduction
  • the usual selenium, BC
  • published studies


  • notes for further work

    11.3: sorry link is bad, here is sure ...:
    //knol.google.com/k/philip-torrance/anti-cancer-selenium-cysteine-compounds/
    but first, do the revisions and see if the link changes .

    11.5: todo.health/se:
    . put in summary first lesson of anti cancer
    any form of se can prevent many cases of cancer if local soil has deficient in se .
    . 2nd point is unproven but worth exploring:
    use of non-toxic forms to prevent more cases with mega-dosing .

    Ghose A, Fleming J, El-Bayoumy K, Harrison PR.
    Enhanced sensitivity of human oral carcinomas
    to induction of apoptosis by selenium compounds:
    involvement of mitogen-activated protein kinase and Fas pathways.
    Cancer Res. 2001 Oct 15;61(20):7479-87.

    it was shown by Hoffman J L (1975) selenium toxicity and methyl group metabolism
    that se-methionine was not metabolized to selenocysteine as readily as methionine


    Whanger PD. Selenium and its relationship to cancer: an update.
    Br J Nutr. 2004;91(1):11-28. (PubMed)
    phil.whanger@orst.edu
    Selenomethionine (Semet) is the major seleno-compound in cereal grains and enriched yeast
    whereas Se-methylselenocysteine (SeMCYS) is the major seleno-compound in Se-accumulator plants
    and some plants of economic importance such as garlic and broccoli exposed to excess Se.
    Animals can metabolize both Semet and SeMCYS.
    Epidemiological studies have indicated an inverse relationship
    between Se intake and the incidence of certain cancers.
    Blood or plasma levels of Se are usually lower in patients with cancer
    than those without this disorder,
    but inconsistent results have been found with toenail-Se values
    and the incidence of cancer.
    There have been eight trials with human subjects conducted
    on the influence of Se on cancer incidence or biomarkers,
    and except for one,
    all have shown a positive benefit of Se on cancer reduction
    or biomarkers of this disorder.
    This is consistent with about 100 small-animal studies
    where Se has been shown to reduce the incidence of tumours in most of these trials.
    Se-enriched yeast is the major form of Se used in trials with human subjects.
    In the mammary-tumour model,
    SeMCYS has been shown to be the most effective seleno-compound
    identified so far in reduction of tumours.
    Several mechanisms have been proposed on the mechanism whereby Se reduces tumours.
    Even though SeMCYS was shown to be the most effective seleno-compound
    in the reduction of mammary tumours,
    it may not be the most effective seleno-compound for reduction of colon tumours.
    Proc Nutr Soc. 2005 Nov;64(4):527-42.
    Selenium in cancer prevention: a review of the evidence and mechanism of action.
    Se is an unusual trace element in having its own codon in mRNA
    that specifies its insertion into selenoproteins as selenocysteine (SeCys),
    by means of a mechanism requiring a large SeCys-insertion complex.
    This exacting insertion machinery for selenoprotein production
    has implications for the Se requirements for cancer prevention.
    If Se may protect against cancer, an adequate intake of Se is desirable.
    However, the level of intake in Europe and some parts of the world
    is not adequate for full expression of protective selenoproteins.

    The evidence for Se as a cancer preventive agent
    includes that from geographic, animal, prospective and intervention studies.
    Newly-published prospective studies on oesophageal, gastric-cardia and lung cancer
    have reinforced previous evidence,
    which is particularly strong for prostate cancer.

    Interventions with Se have shown benefit in reducing the risk of
    cancer incidence and mortality in all cancers combined,
    and specifically in liver, prostate, colo-rectal and lung cancers.
    The effect seems to be strongest in those individuals with the lowest Se status.

    As the level of Se that appears to be required for optimal effect
    is higher than that previously understood to be required to maximise
    the activity of selenoenzymes,
    the question has been raised as to whether
    selenoproteins are involved in the anti-cancer process.

    However, recent evidence showing an association between Se,
    reduction of DNA damage and oxidative stress
    together with data showing an effect of selenoprotein genotype on cancer risk
    implies that selenoproteins are indeed implicated.

    The likelihood of simultaneous and consecutive effects at different cancer stages
    still allows an important role for
    anti-cancer Se metabolites such as methyl selenol
    formed from gamma-glutamyl-selenomethyl-SeCys and selenomethyl-SeCys,
    components identified in certain plants and Se-enriched yeast
    that have anti-cancer effects.

    There is some evidence that Se may affect
    not only cancer risk but also progression and metastasis.



    Se-broccoli similar to se-garlic
    J Med Food. 2003 Spring;6(1):19-26.
    Reduction of cancer risk by consumption of selenium-enriched plants:
    enrichment of broccoli with selenium increases the anticarcinogenic properties of broccoli.
    jfinley@gfhnrc.ars.usda.gov

    Plant-based diets and phytochemicals present in plants
    are associated with decreased risk of cancer.
    Brassica species, and broccoli in particular,
    are associated with reduced risk of several important cancers.
    Broccoli accumulates Se many-fold beyond the concentration of Se in the soil,
    and the chemical form of Se in broccoli
    is similar to the chemical form in high-Se garlic,
    a food with unique chemoprotective properties.
    Se from broccoli grown to accumulate more than 500 micro g Se/g
    did not accumulate in rat tissues
    or increase glutathione peroxidase enzyme activity
    to the same extent as Se salts or seleno-amino acids.
    Se from high-Se broccoli decreased the incidence of aberrant crypts in rats
    with chemically induced colon cancer by more than 50%, compared with controls.
    Se from high-Se broccoli also decreased the incidence of mammary tumors in rats
    treated with 7,12-dimethylbenz(a)anthracene (DMBA)
    and tumor number and volume in APC(min) mice.
    These results suggest that development of methods to increase
    the natural accumulation of Se in broccoli
    may greatly enhance its health-promoting properties.


    Med Hypotheses. 2006;67(2):318-22. Epub 2006 Mar 30.
    Cancer chemoprevention: selenium as a prooxidant, not an antioxidant.
    Rocky Mountain Selenium, Inc.,
    endrake@airbits.com

    Although the average daily dietary selenium (Se) intake in the United States
    is consistently above the adult RDA of 55 microg Se/day,
    supranutritional supplements of 200 microg Se/day have been shown to provide
    chemopreventive benefits against several cancers, particularly prostate cancer.
    The hypothesis herein contends
    that selenium compounds with the greatest anticarcinogenic potency
    are likely to be sodium selenite with Se in the +4 oxidation state
    and methylseleninic acid.
    These compounds exert their cancer chemopreventive effects
    by directly oxidizing critical thiol-containing cellular substrates,
    and are more effective
    than the more frequently preferred (used) supplements of
    selenomethionine and
    Se-methylselenocysteine
    that lack oxidation capability.
    Selenate (+6 Se) the immediate precursor of selenite (+4 Se)
    can be metabolically reduced,
    and although less potent than the +4 Se compounds cited above,
    appears to be a more effective anticarcinogen than organic forms of dietary selenium.
    Apoptosis, an important, Se-induced anticarcinogenic mechanism,
    is accomplished by the direct oxidation of
    vicinal sulfhydryl groups in cysteine clusters within the catalytic domains of
    cellular enzymes (e.g., protein kinase C),
    and by the production of CH3Se-,
    which reacts with O2 to generate superoxide
    and other reactive oxygen species (ROS).
    Activated oncogenes "prime" cells for Se-induced prooxidative apoptosis
    thereby providing the needed margin for "killing" cancer cells
    while leaving normal, healthy cells unharmed.
    Selenoethers, such as selenomethionine and Se-methylselenocysteine
    are not oxidizing agents,
    and first, must be converted to methylselenol (CH3Se-)
    that can be directly oxidized to methylseleninic acid.
    The addition of methioninase, to selenomethionine,
    or beta-lyase to Se-methylselenocysteine,
    rapidly produces significant amounts of methylselenol,
    which may be oxidized to methylseleninic acid
    or may react with O2 to produce superoxide and ROS,
    resulting in anticarcinogenic activities comparable to selenite
    or methylseleninic acid.
    The relatively large amounts of selenomethionine or Se-methylselenocysteine needed
    to produce apoptosis in cancer cells
    compared with selenite or methylseleninic acid
    are a probable consequence of low tissue levels of the required enzymes.
    Even though many studies have consistently shown that
    selenomethionine is an ineffective anticarcinogen
    at doses corresponding to those currently allowed by the FDA,
    it has been chosen as the Se intervention agent in the
    32,500-man (phase III), NCI-funded SELECT trial,
    which tests the effectiveness of dietary supplements of dietary supplements of Se and tocopherol,
    individually or in combination, in the prevention of prostate cancer.
    In 2013, when the data are in,
    the value of using Se supplements for cancer chemoprevention
    is likely to be underestimated.
    11.4:
    Lessons from Basic Research in Selenium and Cancer Prevention
    Journal of Nutrition Vol. 128 No. 11 November 1998, pp. 1845-1854


    Selenium, in the form of selenite or selenomethionine,
    functions as an essential micronutrient at levels of
    [approx] 0.1 ppm (mg/kg) in the animal diet,
    but it becomes a toxin at levels of 8-10 ppm (Jacobs and Frost 1981).
    At the other extreme,
    selenium deficiency is customarily induced in laboratory animals by
    [a dose of less than ] 0.01 ppm Se.

    the effect of selenium deficiency on carcinogenesis.
    The information in this particular topic is not only sketchy
    but also inconsistent.
    [anti-cancer effects unrelated to resolving deficiency issues
    involve dosing at levels ] above dietary requirement,
    usually in the range of 1-5 ppm Se.

    More than 90% of the selenium cancer chemoprevention experiments
    have used either sodium selenite or selenomethionine
    as the test reagent because they are commercially available.

    Both of these compounds are known to suppress carcinogenesis in many animal models
    (Combs 1997, El-Bayoumy 1991, Ip 1986, Medina and Morrison 1988).
    The effect is not organ specific,
    because tumor inhibition has been reported in
    mammary gland, liver, skin, pancreas, esophagus, colon and a few other sites.

    [. similar effects have been shown in humans,
    with significant reductions in occurrences of the major cancers in the U.S. population:
    (
    lung: 54 % (P = 0.04),
    colon: 37 % (P = 0.002)
    prostate: 42 % (P = 0.03)
    )
    . the study was documented by Clark et al. (1996):
    Effects of selenium supplementation for cancer prevention
    in patients with carcinoma of the skin.
    J. Am. Med. Assoc. 1996; 276:1957-1985
    . the Clark et al. (1996) trial used a [a non-methionine form]
    ( Selenomax¨ from Nutrition 21 La Jolla, Calif.)
    --
    . according to Life Extension: A Practical Scientific Approach (p#671)
    Selenomax¨ is not your typical selenized yeast:
    . most selenized yeasts are primarily selenomethionine
    which is less effective than non-organics (eg selenite)
    at elevating deficient levels of glutathione peroxidase;
    an exception is selenized yeast from Nutrition 21
    which exhibits good results in this test .
    . while being organic, Selenomax¨ is most likely a seleno-trisulfide
    and not primarily selenomethionine .
    [or a di-methyl-di-selenide
    . according to Dr.Whanger's ref's
    yeast's se forms may vary like so:
    0...4 % selenate
    0...25 % selenite
    6...20 % Se-methylselenocysteine
    23...63 % (Nutrition 21: 16 %) se-methionine
    13...21 % (Nutrition 21: 11 %) se-cysteine
    13...51 % (Nutrition 21: 81 %) other:
    seleno-lanthionine,
    seleno-cystathionine,
    {gamma}-glutamyl-seleno-ethionine,
    Se-adenosyl seleno-homocysteine,
    Se-ally selenocysteine,
    Se-propenyl selenocysteine,
    and unknown.
    #46 Speciation of selenoamino acids and organoselenium compounds in selenium-enriched yeast
    using high-performance liquid chromatography-inductively coupled plasma mass spectrometry.
    J Anal Atomic Spect12 :785 Ð788,1997 .
    #47 Analytical selenoamino acid studies
    by chromatography with interfaced atomic mass spectrometry and atomic emission spectral detection.
    Fresenius J Anal Chem362 :447 Ð456,1998 .
    #50 Identification of the principal selenium compounds in selenium-enriched natural sample extracts
    by ion-pair liquid chromatography with inductively coupled plasma- and electrospray ionization-mass spectrometric detection.
    Anal Commun36 :249 Ð252,1999 .
    #54 Characterization of selenium species in biological extracts
    by enhanced ion-pair liquid chromatography with inductively coupled plasma-mass spectrometry and by reference electrospray ionization-mass spectrometry.
    Spectrochimica Acta54 :1573 Ð1591,1999 .



    what are selenotrisulfides?
    Selenocompounds in Plants and Animals and their Biological Significance
    Journal of the American College of Nutrition, Vol. 21, No. 3, 223-232 (2002)

    . when selenite was given to animals,
    it represented only 14% of the overall quantity of selenium [found in tissues]
    and the seleno-trisulfide metabolites,
    as a percentage of total selenium absorbed, were:
    ( seleno-di-cysteine: 10 %;
    , mixed seleno-tri-sulfide of cysteine and reduced glutathione: 14 %;
    , seleno-di-glutathione: 8 %
    ). [seleno-tri-sulfides are apparently 1 part se, and 2 parts
    sulfer-based organic ]

    . selenized yeast often contains mostly Selenomethionine
    but the amount can vary markedly depending upon the growth conditions.
    [ eg, incorporation of selenite with cysteine, cystine and glutathione
    into Seleno-di-cysteine and seleno-di-glutathione
    is greatly affected by pH. {Czauderna, Samochocka}
    ] [and may vary on storage conditions:
    All the yeast-based supplements and one yeast-free supplement
    formed S-(methylseleno)cysteine on heating
    (from a reaction between di-methyl-di-selenide and cysteine or cystine)
    -- there were similar speciation patterns observed between
    yeast-based supplements subject to extended storage
    and those heated briefly at elevated temperatures . ]

    . plants and animals may contain some inorganic se;
    when inorganics are found, they are usually selenate .

    . most plants contain se-methionine,
    which animals can uses as either se or methionine
    [hence the reason animals short on protein (esp'ly methionine)
    will still be deficient in se after getting se-methionine]

    . animals contain mostly variants of se-cysteine;
    any se-methionine used as se rather than protein
    will soon be reduced and reconstructed as some se-cysteine .

    . the few plants that contain mostly se-cysteine (esp'ly Se-methylselenocysteine)
    -- when they contain any se at all --
    include garlic, onions, wild leeks, and broccoli florets or sprouts .
    ]
    . the Nutrition 21 Selenomax¨ trial was
    double-blind, randomized, placebo-controlled, and involving
    1312 basal cell or squamous cell carcinoma of the skin patients (mostly men)
    from a selenium-deficient area (eastern coastal plains of USA).
    . the blinded phase of the trial was stopped early
    primarily because of the apparent reductions in total cancer mortality
    and total cancer incidence in the selenium group .

    . it was originally set up to determine whether
    selenium would decrease the incidence of skin cancer;
    and while it failed to show any effect there,
    it did show that giving se to se-deficient people (200 µg of selenium per day)
    was capable of significant harm reduction:

    reductions in total cancer incidence:
    (77 cancers in the selenium group
    vs 119 in controls [RR, 0.63; 95% CI, 0.47-0.85])

    reductions in total cancer deaths:
    (29 deaths in the selenium treatment group
    vs 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]) .

    the scientific conclusion:
    [11.4:
    . what was proven here was not that increasing se decreases cancer risk,
    but that being se deficient does increase cancer risk .
    . it's an essential mineral, and plants don't need it,
    so the only sure source is seafood and or supplements .
    ]

    . one reason for the variation of success could be
    the degree to which apoptosis is involved or prevented;
    eg, calcium channel blockers can inhibit apoptosis
    and increasing doses of them are known to
    increase the risk of cancer in the elderly . [48]
    Ganther H. E., Lawrence J. R.
    Chemical transformations of selenium in living organisms.
    Improved forms of selenium for cancer prevention.
    Tetrahedron 1997; 53:12299-12310


    11.12:
    web.health/se/yolk and whey not a sure source of se:

    . no it does depend on the animal's diet .

    J APPL POULT RES 2009. 18:151-157. doi:10.3382/japr.2008-00069
    Poultry Science Association
    Selenium contents of eggs from broiler breeders supplemented with
    sodium selenite or zinc-L-selenium-methionine
    This study evaluated the effects of sources and levels of Se
    on egg production and Se concentration in eggs.
    A comparison between treatments with single Se sources
    demonstrated that the concentration of Se in eggs
    followed the increased levels in the feeds when ZnSeMet was used.
    However, the supplementation of a combination of sources
    (Na2SeO3 and ZnSeMet) produced similar egg Se concentrations.
    Laying hens were fed a diet that contained either 0.10 mg/kg natural selenium,
    0.10 mg/kg natural selenium plus
    0.32 mg/kg selenite selenium,
    or 0.42 mg/kg natural selenium.
    After the hens had been fed these diets for 180 days,
    tissues and eggs from hens fed 0.42 mg/kg natural selenium
    contained significantly more selenium than
    tissues and eggs from hens fed the selenite selenium.
    . when hens were fed 0.1 mg/kg of selenite selenium,
    significantly more selenium was present in the yolk
    than in the white of the egg.
    Selenium in the white resulting from the selenite feeding
    could be removed by dialysis but not that in the yolk.

    Comparison of Selenium Levels and Sources
    and Dietary Fat Quality
    in Diets for Broiler Breeders and Layer HensPoult Sci 2008. 87:2605-2612. doi:10.3382/ps.2008-00174
    . to study the effects of Se sources,
    in interaction with dietary level of Se or dietary fats
    on performance, Se incorporation into
    tissues (blood, liver, breast muscle, and egg) and eggs,
    hatchability, and glutathione peroxidase (GPX) activities
    in tissues and blood.
    Both experiments involved a 3 x 2 factorial arrangement of 3 Se sources
    (selenite, Se yeast, or B-Traxim Se)
    and either 2 levels of each source (0.1 or 0.3 mg/kg)
    or 2 fats (fresh or oxidized).
    Egg production was not affected by Se source or dietary fat in both experiments.
    Egg production was greater in breast muscle of layers.
    It is concluded that broiler breeders require supplementation of 0.3 mg/kg of Se,
    and that there are numerous measurable advantages
    in using organic rather than inorganic sources for both breeders and layers.