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SOD2, CYP1B1, (PAH) Connections

Discussion in 'Genetic Testing and SNPs' started by LaurieL, May 31, 2013.

  1. LaurieL

    LaurieL Senior Member

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    SOD2 = mitochondrial superoxide dismutase

    * Is usually found present with catalase except in the cerebral cortex and thyroid.
    * Is also found in E coli, ferrous III enzyme.
    * Is destroyed by gastric acid in oral supplementation.
    * Often referred to as Mn.-SOD

    * The mitochondrial electron transport chain produces superoxide as a byproduct. Superoxide is a free radical, and without SOD2, the mitochondrial membrane is then under direct exposure to hydroxy- radicals with little protection from oxidative damage. It is here that I wonder if histamine problems originate, correlating with lack of SOD2, the body recognizing the oxidative damage to the mitochondria and lack there of, of SOD2, and in an attempt to remedy the situation by producing more histadine to bind maganese, or some similar mechanism. Histidine being the precursor of histamine, overloading the bodies ability to dispose of histamine, due to the high levels being generated. And of course there are disposal mutations to consider as well as well as maganese levels and transport. (What I can offer, is my own personal observation, the more antioxidants I take, the less problems with histamine I have.)

    * SOD2 being connected to CYP1B1, because of PAH exposure and the oxidative damage occuring at higher levels due to mutations. SOD2 could easily be connected to many of the detoxification markers currently being tested and could be one of the top reasons why someone could get so ill. We have already read that knockout mice lacking SOD2 don't survive, other species can. So it may not explain longevity and disease, but with mutations down regulating its function, its clear that damage will occur and disease could manifest. And the first hit would be on the mitochondrial membrane.

    CYP1B1

    * Is associated with resistence to certain chemotherapy drugs.
    * Avoid PAH exposure if mutation occurs.
    * Part of Phase I conjugation.
    * Is a monooxygenase which catalyzes drug metabolism, synthesis of cholesterol, steroids, and other lipids.
    * Involved in the hydroxylation of estrogens as well. Remember estrogen is a steroid hormone.
    * Association of mutations to colorectal cancer, multiple myeloma, breast cancer, glaucoma, and when occurring concurrently with a mutation in glutithione S-transferase, Non-Hodgkins Lymphoma.
    * Exposure relevant ploymorphisms include CYP1B1, EPHX1, NQO1, GSTM1, GSTP1, and GSTT1.
    * Correlation to endothelial dysfunction in the presence of yet another cholesterol associated polymorphism, APOE.

    ACAT1

    It would seem that many in the Autism forums do not have this particular mutation, (population frequency). I have to wonder about the ME/CFS arena. This would be a good poll for someone......hint, hint...

    None-the-less, it is a cholesterol ester gene and I have it, but my son does not. Which leads to more cholesterol info. It also pertains to my own investigations through mutations in the APOA1.

    I have hypocholesterolemia. Low cholesterol, hangs around 138. My son is the opposite. BUT, in my family, we have this thing with our toes, called syndactly. Ours is very minor, and not noticable unless we point it out. But in many of us, our 2nd and third toes are fused just at the bottom, so they look normal, but if you feel them, they are not normal. This is something that has always been accepted, and none of our physicians have noticed it either. Nor did we think to mention it.

    LDL is important...too low of levels and you lose protection against infection, as it is protective to RBC's from bacterial endotoxin.

    In looking at this, since I have encountered so many other cholesterol related mutations, I pursued this further and found the DHCR7 gene. This gene is directly correlated to Smith-Lemli-Opitz Syndrome, or SLOS. Interestingly, my son and I both have the mutation linked to SLOS. In the link, notice the reference to Autism as well.

    DHCR7 rs4316537, risk = A

    http://www.greatplainslaboratory.com/home/eng/FAQ-cholesterol.asp

    Again, I was intrigued by yet another cholesterol mutation, so I pursued others.

    Hypercholesterolemia is high cholesterol in the blood. Familial hypercholesterolemia is genetic, there are other types, such as polygenic. If mutations are found in any of the following, cascade testing of other cholesterol genes should be pursued in first generation family members. They mention a 12 LDL-c gene score. If anyone knows what that is, I am out of time, and would appreciate the help.

    http://ghr.nlm.nih.gov/condition/hypercholesterolemia

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102597/

    APOB
    LDLR, recpetor
    LDLRAP1, receptor
    PCSK9
    ANGPTL3
    ABCG8, rs11887534 risk = C

    So I looked those up, and I do have some, but my son's mutations are off the chain so far, and I do have some work to identify the homozygous mutations still. My mutations are clustered in the receptor and transport regions, where as his are clustered in the regulation of production.

    Where I have not given specific rs numbers, its not that I don't have them, there are just many of them. You can correlate the readout with what 23andme gives you, and SNPedia for the latest correlations and risk alleles.

    There are some other genes I didn't get a chance to look into. Those being ID1, SQLS, SQLE, and GLPT.

    Vitamin D is responsible for binding cholesterol, another hint @ some help....
     
    Sidereal, Tunguska, cigana and 4 others like this.
  2. LaurieL

    LaurieL Senior Member

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    CHOLESTEROL, , GSTP1, 17B-ESTRADIOL, & COMT, MAO-A, SOD2:
    ADRENOCHROME HYPOTHESIS


    17B-Estradiol is Estradiol, Oestradiol, and also referred to as E2.

    There are three classes of estrogen (and you men need to pay attention tooo_O)

    1) E1 (estrone) Most prominent in post-menopausal women.
    2) E2 (estradiol) Most potent and most prominent estrogen in women of reproductive years.
    Also found in males and is the active metabolite of testosterone. Levels are
    comparable to the levels found in post-menopausal women.
    3) E3 (estriol) Most prominent in pregnancy.

    Estradiol or E2 is a steroid hormone and is derived from cholesterol.

    It is also a catechol hormone. There is a direct association between catechols and cholesterol.

    Catechol being further defined as a difunctional benzene.

    Catechols will produce quinones with the addition of nitrates. Quinones being connected to the adrenochrome hypothesis. see more info here...

    An example of its chemical function that I found, is one that everyone is familiar with. In the case of an apple or a potato, when it is cut, the catechols in the apple or potato, upon exposure to oxygen (oxidation), will oxidize to a reddish-brown to dark brown melanoid pigment, which is a derivative of benzoquinone. Benzoquinone is considered an antimicrobial, in which the injured(cut) apple or potato slow bacterial growth due to the injury.

    Why is this important? I believe those of us with mutations in the CYP1B1, SOD2, and GSTP1 genes, and/or problems with estrogen receptors, will be predisposed to oxidative stress prone to the formation of quinones. Especially that of CYP1B1 and GSTP1. I am finding correlating mutations leading to a specific subset of disease. Although my research covers that of my son or myself specifically, I believe upon looking at your own mutations, you will also find additional subsets to your own personal situation. I don't believe there is one way to ME/CFS, an answer that fits all of us, but there is a significant proportion of us whom have these specific mutations in our detoxification pathways. I would be curious to see what that proportion really is in this forum.

    Back to catechols...

    Manufactured catechols are found in pesticides (50%), and perfumes and pharma drugs bringing up the rest. I mention this, because pesticide use has gone up exponentionally as well as pharma drug use, and not to mention incorporation into some of our food supply, and this seems to correlate with the datelines of emerging illnesses and precosious puberty occurence spikes. But I digress...

    Catecholamines are epinephrine (adrenalin), nor-epi ( nor-adrenalin), and dopamine, all produced from tyrosine and phenylalanine. Catecholamine secreting cells use several reactions to serially convert tyrosine to LDopa, and then to dopamine. Depending on the cell type, dopamine may be further converted to nor-epi or even further to epinephrine. It is here I wonder if some of the problems we experience with anxiety and abnormal energy surges center on; And warrants consideration of those of you in which experience this due to starting methylation recommendations. Also, IMO, addressing the detoxification mutations you have present should be addressed at the same time as starting methylation. IMO, this would make the process a whole lot easier on one trying to achieve detoxification, as methylation is only one pathway in detoxification.

    The correlation to MAO-A...

    High levels of catecholamines can also be caused by mutations/deficiency of MAO-A. MAO-A is one of the enzymes responsible for the degradation of these neurotransmitters, thus its deficiency increases the bioavailablility of these considerably. This can occur in the absence of pheopchromocytoma, neuroendorcine tumors, and carncinoid syndrome, but looks very similar to carcinoid syndrome. All of which have been considered in my illness.

    Back to Estradiol or E2...

    Estradiol affects the production of several proteins, including lipoproteins, binding proteins, and proteins responsible for blood clotting.

    As the mechanism of action,defined by wikipedia, Estradiol binds well to both estrogen receptors, ER alpha, and ER beta, as compared with the other estrogens outlined in the beginning. Estradiol enters cells freely and interacts with the cytoplasmic target cell receptor (ER). Estradiol can enter the nucleus of the target cell and regulate gene transcription, which then leads to the formation of mRNA. The mRNA interacts with ribosomes to produce specific proteins (those mentioned above) that express the effect of estradiol upon the target cell.

    And lets not forget the role of estrogen and the adrenal medulla.

    Enter GST or Glutithione S-Transferases...

    GST's are part of a multi-gene family of enzymes which catalyze the conjugation of glutithione to electrophillic, and thus most hydrophillic xenobiotics to inactivate them. By inactivating them, this prevents the formation of adducts and the subsequent damage to DNA. Adducts being defined as metabolites containing the original molecules and also containing the additive molecules, and can be very reactive and there for very damaging. This includes but is not limited to ROS.

    GSTP1 is found to be associated with the estrogen receptor status in breast cancer studies. (Saata, et.al., 1992), (Whelan et.al., 1992)

    GSTP1 in actively involved in the conjugation of E2 or estradiol. GSTP1 breaks down E2 into semi-quinones and quinones.

    COMT breaks down estradiol, the catechol hormones, by methylation.

    CYP1A1, and CYP1B1, break down E2 by hydroxylation.

    "Based on respective rate constants, CYP enzymes were thought to be less active than COMT, but what they are finding is the opposite. CYP's are now considered to be the most active enzymes overall since they not only initiate but also drive the pathway that results in the O-demethylation of two out of the three metabolites of estrogen, as well as the oxidation of catechol estrogens to estrogen semiquinones and quinones." (Katherine Vega)


    Estradiol has complex effects on the liver and can lead to cholestasis. Something of which runs in my family. It is also a common side effect of Ciprofloxin, a fluoroquinone. I will bet you can correlate the genetic traits outlined here to this side effect in taking cipro.

    Estradiol is also correlated to uterine fibroids/ leiomyomyata. Which also run in my family. I developed them shortly before becoming ill, and then CFS.

    As an aside...

    Pomegranate binds preferentially to ER alpha over Estradiol.

    Quercitin selectively binds ER beta, and directly promotes apoptosis of abnormal cells.

    Green tea, can be beneficial or detrimental. If you are prone to the mutations in which are not functioning as they should with catechols, then green tea may then promote the quinone formation.

    Resveratol affects the cellular function at multiple levels, ranging from interaction with detoxification enzymes, such as GSTP1, and transcription by targeting factors such as ER beta. (TZE-CHENHSIEH, et. al., 2008)
     
  3. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    Any idea of how to "by-pass" (using yasko jargon) or support these mutations? Just with resveratrol etc? I imagine juicing chard must have a possitive impact in the detox pathways, if it does not I am drinking this awful grass-tasting beverage for nothing!

    This is really impressive, LaurieL, :eek: dont stop now!
     
  4. LaurieL

    LaurieL Senior Member

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    Thank you! I have little time, so the going is slow, but it is still on-going!! Gotta pay the bills first. :)
     
  5. PDXhausted

    PDXhausted Senior Member

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    LaurieL, thank you thank you for sharing your research! So appreciated and interesting!

    23andme implies that if you have a COMT polymorphism (specifically rs4680), that you will get greater benefit from green tea polyphenols because the polymorphism will slow the breakdown of the polyphenols, which seems to have some impact on risk of breast cancer. But would a COMT polymorphism encourage quinone production though?

    https://www.23andme.com/you/journal/pre_breast_cancer/overview/

    Based on this study:
    http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&term=14612555
     
    LaurieL likes this.
  6. LaurieL

    LaurieL Senior Member

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    Yes, I think so but at this point in time, I cannot however differentiate between the different rs#'s associated with Yasko's results and what the pathways may do in each scenario. It is my intent to do so.

    If you have a COMT mutation...and green tea restores or upregulates CYP1B1...

    Estradiol is broken down into two metabolites, both by CYP1B1. In one pathway, Estradiol forms 4- hydroxy-estradiol. By COMT, 4- hydroxy-estradiol is then converted to 4-methoxyestradiol and excreted. But if COMT is slowed down, and you restore/upregulate CYP1B1, then 4-hydroxyestradiol by CYP1B! forms Estradiol 3,4-semiquinone. At this point, if oxidized, it will form superoxides, or it can go through redox cycling to Estradiol 3,4-quinone and then by the GST's to form glutihtione conjugates. So if you have mutations affecting GST's then you can't form glutithione conjugates. Leading to the quinones.

    I should stop here, but there are two other pathways in which can also break down estradiol. Those being glucuronosyltransferases, and sulfotranferases. Glucuronidation and sulfation being yet another two detoxification pathways, and I am very curious to see what mutations may do to the flow of the pathway at these points as well.

    My workweek starts friday. See ya next week!

    LaurieL
     
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  7. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    Some time later and... I have homozigous CYP1B1, SOD2, and GSTP1! :eek:
     
  8. helen1

    helen1 Senior Member

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    Hi Laurel
    Thanks for your amazing research! And PDX too for your interesting links.
    Laurel, I didn't quite understand the part about the various antioxidants. If they bind to estrogen receptors, that's bad, right?
    And what is your conclusion about resveratrol? Helpful or not helpful?
     
    Beyond likes this.
  9. roxie60

    roxie60 Senior Member

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    Is the minor allele always the risk allele?
     
  10. Valentijn

    Valentijn Activity Level: 3

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    No, usually neither allele is a risk allele.

    But sometimes there's research showing that one allele or the other is associated with the gene being expressed a bit differently. Usually it has to be a missense or other mutation which results in a structural change of the protein that the gene creates.
     
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  11. zenmaster

    zenmaster

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    I am interested in this thread as well as they relate to my mutations as well. Per the estrogen metabolism front, I would assume those of us would benefit from taking DIMM, is that correct?

    I may add Resveratol to my ever growing list of supps...
     
  12. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    Yes, DIM is an inducer of all the CYP1 enzymes/genes, in which I have lots of homozigous mutations. The poster Gestalt have had good results using it. It will lower bad estrogen and convert it into good estrogen, which means virility and more free testosterone for men. This supplement can only benefit you if taken at reassonable doses.

    I am investigating Resveratrol, so far it seems like an interesting supplement since it would also enhance the HPA axis and Endothelial Nitrix Oxide Synthase (I have NOS mutations too) on top of the detoxificaction enzymes, but I am not yet sure of the implications on estrogen metabolism and the CYP genes/enzymes. I mean, what if it increases the bad estrogen? Then taking it with DIM would solve the issue. But if it lowers bad estrogen, taking DIM with it could make estrogen too low, which is a problem.

    http://www.karger.com/Article/Abstract/89487

    http://www.sciencedirect.com/science/article/pii/S0022395612003391

    http://www.sciencedirect.com/science/article/pii/S027869150800673X

    The effects of resveratrol on human physiology seem to be greater than what I thought. It affects the adrenals, being an endocrine disruptor, and decreases MAO A activity over time (good for me because of my genes). It is not clear if the benefits outweight the possible bad effects.

    Furthermore, its well established that it inhibits CYP1A1, CYP1A2 and CYP1B1 all of which I have double mutated. In short DIM induces these enzymes, whereas Resveratrol inhibits them, so it all depends of these mutations mean up or downregulations.
     
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  13. cigana

    cigana Senior Member

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    This is interesting to me because I have a polymorphism in CYP1B1, COMT, GSTP1 and am homozygous for SOD2.
     
  14. vacuna

    vacuna

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    Hi @LaurieL ,

    I ran across your post while searching for hypercholesterolemia. A month ago, we ran some blood tests on my 10 year old daughter because of low temps and lethargy. I was shocked when her LDLs came back at 472; neither my husband nor I have ever had LDLs this high (my husband never has been out of range, and mine have only seemed to be elevated because of thyroid issues).

    Do you know of anything that can be done to get the body to use up the LDLs?


    I couldn't find these SNPs on our MTHFRSupport reports. Can you tell me where you obtained the test? We recently ran a 23andMe test for her, but I am beside myself with what is going on and whether to be concerned.

    I appreciate any insight you have to offer.
     
  15. Peyt

    Peyt

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    Hi Vacuna, ACAT is a SNP both on 23andme and Yasko's test. Did you get the 23andme results back yet?
     
  16. vacuna

    vacuna

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    Hi @Peyt,

    I've attached the results of the 23andMe results run through Genetic Genie. For the SNPs where dad and I were negative, I filled in DD's. There were a few, however, that I couldn't guess because either dad or I had mutations.
     

    Attached Files:

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