Personalized Medicine
Transcription
Personalized Medicine
Implications of Genetic Testing for Alternative Healthcare Dr. Amy Yasko May 2005 Many factors influence our susceptibility to disease. These include our stress load, our environment and the toxins we absorb from it, the total number of infectious agents we are exposed to as well as our underlying genetic susceptibility to these diseases. It is important in this day and age to address all the contributing factors to these multifactorial diseases. A given individuals the risk of Multifactorial Disease is dependent on a number of factors •Environmental •Genetic •Infectious •Stress DISEASE Stress + Infectious agents + Toxins + Underlying genetic susceptibility = Disease Examples of Multifactorial Disease Atherosclerosis vs.. Autism • Genetic • MTHFr • Infectious • Chlamydia pneumonia • Streptococcus • Stress • Inflammatory Mediators • Glutamate • Improper Calcium Regulation • Improper CO2 Regulation • Environmental • Cholesterol • Cardiovascular Inflammatory Disease • Genetic • MTHFr • Infectious • Viral: MMR, Herpes • Bacterial • Stress • Inflammatory Mediators • Glutamate • Improper Calcium Regulation • Improper CO2 Regulation • Environmental • Heavy Metals • Neuroinflammatory Disease Alzheimer’s Disease • Associated with age • While APOE2 is an underlying risk factor • Risk is heterogeneous and independent of APOE • Risk may be related to “other genes or environmental factors that can be investigated” JAMA September 15, 2004 The combination of components that interact to cause multifactorial diseases may be different in every individual. There may be slight or enormous changes in the relative contributions of each of these components to disease. Genetic Testing as a Way to Evaluate the Genetic Contribution of Multifactorial Disease Genetic Screening is the wave of the future for both Alternative Healthcare as well as Allopathic medicine F.D.A. Issues a Guide to Gathering Genetic Data By ANDREW POLLACK Published: March 23, 2005 The Food and Drug Administration took a significant step yesterday toward the development of so-called personalized medicine, in which drugs would be tailored to individuals based on their genetic profiles. The agency issued guidelines for pharmaceutical companies intended to encourage them to gather and submit information about how genetic variations affect the way people respond to their drugs. Drug companies have been somewhat reluctant to do this, agency officials said, from fear that the government might use the information to limit the market for their drugs. Drug makers have also worried that the F.D.A. might block approval if, say, a drug was shown in a laboratory test to activate a gene that might be involved in cancer. To reassure drug companies, the F.D.A. has said that most of the genetic information will not be considered in regulatory decisions. Instead, the agency said, the information will be used to help the agency learn about the new science of tying genetic variations to drug response, a field called pharmacogenomics or pharmacogenetics. "Companies either weren't doing that work because they weren't understanding its regulatory status or they weren't submitting it to us," Janet Woodcock, the F.D.A. acting deputy commissioner for operations, said in an interview. She added, "I can't tell you how important it is for medicine that we move into this paradigm." Edward Abrahams, executive director of the Personalized Medicine Coalition, a Washington group of companies, academic institutions and others that aim to promote the new field, hailed the F.D.A. guidelines as a milestone. "The government is now the advocate for personalized medicine in an official way." Pharmacogenomics is still in its infancy. It is well known that a particular drug might work for some people but not for others, or might cause side effects in some people but not in others. But so far there has been little testing of patients for genetic variations that could predict such reactions, which would allow drugs to be given to appropriate patients and reduce side effects. Both disciplines (Alternative and Allopathic Medicine) will take advantage of the strides made in the Human Genome Project that allow us to utilize simple genetic tests to look at our genetic weaknesses. The goal of the Human Genome Project was to identify all the approximately 30,000 genes in human DNA and to determine the sequences or “spelling” of the 3 billion chemical base pairs that make up human DNA. This project was completed in June of 2000. As a direct consequence of having the complete sequence of the human genome, research has focused on identifying particular genes that are involved with specific diseases. The challenge is to identify disease causing genes and clarify their roles. “The advent of microarray technology has accelerated the pace of gene expression analysis, allowing the simultaneous analysis of thousands of genes.” (Salowsky, R., BioPharm International, May 2004). The Ultimate Gene Gizmo: Humanity on a Chip Commercial genomics reached a landmark last week, and several companies are jostling to share the limelight. Affymetrix Inc. of Santa Clara, California, announced that it is now selling the first research device that contains a complete set of 50,000 candidate genes covering the entire human genome. The GeneChip, as this microarray is called, can be used to measure the activity of all known human genes in a biological sample. Meanwhile, another California company, Agilent Technologies Inc. of Palo Alto, has begun distributing its own human genome array as an Experimental prototype, and since June NimbleGen Systems Inc. of Madison, Wisconsin, has been using yet Another whole-genome setup to support a DNA-scanning Service at a lab in Iceland. These arraymakers use a variety of techniques to attach minuscule dots of DNA onto glass slides, silicon wafers, or nylon membranes. When exposed to a mix of RNAs from a biological sample, each DNA latches onto the RNA that matches its sequence. The RNA carries a fluorescent tag, marking the place where it attaches. Based on the location and intensity of the signal, researchers can tell which gene is the source and how active it is. Fear Of Genetic Testing • Inability to address the condition • Insurance • Job Discrimination Genetic testing falls short of public embrace. NY Times (Print). 1998 Mar 27;:A16. No abstract available. PMID: 11647298 [PubMed - indexed for MEDLINE] Ethical aspects of genetic testing. Whittier Law Rev. 1998 Winter;20(2):411-22. No abstract available. PMID: 11660804 [PubMed - indexed for MEDLINE] Refusal of employment or insurance. Am J Hum Genet. 1997 Oct;61(4):A56. No abstract available. PMID: 11644971 [PubMed - indexed for MEDLINE] Is knowledge always good? Genethics News. 1996 May-Jun;No. 12:6-7. No abstract available. PMID: 11655116 [PubMed - indexed for MEDLINE] Screened out of coverage? Genetic discrimination in health insurance is emerging as companies deny coverage to people whose genes give them a greater chance of getting sick later on. Genetic predisposition, the argument goes, is a pre-existing condition. With the health insurance system as attentive to the bottom line as it is, some observers predict that unless safeguards are put in place, genetic screening could become routine for coverage or for continued coverage. It seems certain that some will be shut out of the health-care system. What mechanisms will protect those forced out, and who will pay the cost? Will society have the will--and the opportunity--to decide? In the workplace, genetic discrimination is beginning to surface as employers refuse to consider people with predispositions to illnesses. Employees who may become ill later on could cost a company in higher health insurance rates and lost productivity. Medical privacy is a closely related issue. Last spring two Marines were court martialled because they refused to submit to DNA classification, claiming it violated their privacy. Though the Pentagon said the information would be used only to help identify the casualties of war, many see a danger in genetic data routinely collected and stored. Civil libertarians fear that genetic test results obtained for one purpose may be used against the person later on. What if genetic screening of an 18-year-old soldier revealed the gene linked to Huntington disease, an incurable degenerative condition that strikes in middle age? When the soldier was back in civilian life, would an insurance company or employer have access to the data? And what if people do not want to learn of their genetic predisposition, lest they find out they are at risk of developing an incurable condition? One Illinois man committed suicide after learning he carried the gene for Huntington disease. Anticipating these problems, the Evangelical Lutheran Church in America is working to prepare pastors and congregations to sort out the issues and work to minimize the damage--both locally and throughout society. The Division for Church in Society is developing congregational study materials on genetics, planned for distribution in fall 1997. "We are going to help illuminate this controversial and urgent topic that's going to have profound consequences in ordinary people's lives," says Mary Solberg, project leader. A professor of religion at Haverford [Pa.] College, she worked for five years as the editor of the Encyclopedia of Bioethics. However, despite the promise of lifesaving medical breakthroughs, some implications of the research have raised concerns within the Jewish community -- and not only for the diseases themselves. These concerns are primarily about genetic discrimination in insurance or employment. Since the breast cancer research results first appeared, Hadassah has understood that fear of genetic discrimination might keep individuals from undergoing genetic testing to gain health information. We have heard this fear expressed, throughout the United States, in our Hadassah-sponsored community health forums and via frantic telephone calls received by our Health Education Department in New York. Individual stories are easy to find. One of our own Hadassah Board Members who has a strong family history of breast cancer will not take a genetic test, for fear her daughter may be at risk for discrimination. Such stories are reported regularly in the Jewish press. Major national newspapers also report evidence of this fear. About a month ago The New York Times featured a story entitled, "Genetic Testing Falls Short of Public Embrace," which detailed the current status of what was to be a potentially $100 million-a-year commercial genetic testing market. The article claimed biotechnology companies that had developed tests to identify genetic mutations -- like the ones found for breast cancer in the Jewish community - had expected a deluge of clients. Instead, the companies reported that they had not seen much business in the past year. Individuals interviewed in the story stated that fear of discrimination played a key role in their decision not to take a test, even where they believed it could provide critical medical information. A more disturbing article ran in Ha'aretz, the Hebrew language daily in Israel. The title of the story was "Come to Israel to test your genes." It read, "A new kind of tourism is developing at Israel's oncology clinics which specialize in genetic testing ..." It described the phenomenon of Americans traveling to Israel for genetic testing, where they are not afraid that insurance companies can get access to the results. Mr. Chairman, it is a terrible Catch-22 that individuals who are simply seeking information to better care for their health may be denied the health insurance coverage they need to do so. It is particularly unfair with genetic information. The presence of a genetic mutation does not necessarily mean the individual carrying it will ever get the disease. A significant percentage of those carrying a B-R-C-A1 mutation will never get breast or ovarian cancer. Nor does the lack of a genetic alteration indicate that an individual is risk-free. We need a way not only to diagnose Genetic Susceptibility but also to way to treat it Four basic steps have been outlined to work from information in our genes to developing personalized medicine. • Defining the functional elements of the human genome • Determining which genes or pathways are altered in a disease state • Discovering inherited sequence patterns contributing to disease • Applying genomics information to improve clinical practices” • (Wills, R, Modern Drug Discovery, June 2004). The long term goal of both molecular medicine as well as molecular nutrition is to have personalized medicine that takes into account an individuals genetic, environmental and infectious disease profile. Personalized medicine enables your cells get the specific communication that they need to be balanced. “individualized healthcare, once a seemingly utopian fantasy, is steadily gaining ground as a rational approach…” (Nature Medicine, June 2004). Molecular medicine will use sophisticated drugs that are concerned with precise mechanisms of action to accomplish this task. “We’re saying if we know what changes in genetic make-up drive a particular disease, then we can design a drug tailored for the individual requirements of that patient.” (Burke, M., BioPeople Sept., 2004). In addition Molecular medicine will use genetics to help to define which individuals can benefit from existing phamaceuticals Improved diagnostics permit better drug dosing to identify the percentage of patients that will respond to customized treatments. “Though the cost and logistics of implementing individualized therapy may appear to be prohibitive…the value of targeted therapy ..and the appeal of customized therapy is evident.” (Nature Medicine, June 2004). This is underscored by the recent finding that only patients with a certain genetic makeup gain any benefit from particular commonly prescribed drugs. The study helps to support the concept of personalized medicine, the choice of drugs that work best for an individual patient based on genetic testing. (Chasman, D., JAMA, Sept. 2004) Special section on human genetics: With your genes? Take one of these, three times a day Truly 'personalized' medicine remains a distant goal. But researchers are now thinking about how to use genomic data to avoid prescribing drugs that may kill, or won't work. By Alison Abbott Nature 425, 760 - 762 (23 October 2003); doi:10.1038/425760a It causes at least 100,000 deaths each year in the United States, and is responsible for more than 10% of hospital admissions in some European countries. But this isn't some terrifying emerging infection, it's the annual toll inflicted by adverse reactions to prescription drugs. What's more, millions of people are being treated with drugs that, for them, will never do much good. Beta-blockers, given to reduce blood pressure, are ineffective in one-third of patients; many antidepressants don't work in half of the people who take them. The blame lies largely with our genes, which help to determine the way in which we react to drugs. Small genetic variations between people — or polymorphisms — can alter the behaviour of proteins that carry a drug to its target cells or tissues, cripple the enzymes that activate a drug or aid its removal from the body, or alter the structure of the receptor to which a drug is supposed to bind. Variation in immunesystem genes can also influence how particular drugs are tolerated. Together, these subtle genetic variations mean that the dose at which a drug will work may vary hugely from person to person. And with today's 'one-size-fits-all' prescribing, that can lead to life-threatening adverse reactions or to a drug completely failing to do its job. Molecular nutrition uses natural products to effect cellular and molecular processes. “Most chronic diseases are related to cellular alterations which can, in part, be influenced by nutrients. “ (International Society for Molecular Nutrition and Therapy). RNA based therapies should be a key factor in helping develop personalized nutrition based on the results of the completed Human Genome Project. A new field of Bioinformatics is developing and information about millions of nucleotides is now stored in huge databases that new medicine will be based on. It would appear that RNA’s function might be as the “mother of all information networks” (Zweigler, G., Transducing the Genome McGraw Hill, 2000). One area or variable that has been sorely overlooked is enhancing our natural cell: cell communication. As we attempt to facilitate the communication between our cells we can reduce some of our underlying genetic susceptibility to disease. We are all familiar with the game of “telephone” where one child whispers a message to the child sitting next to him, who in turn whispers the message to the child sitting next to her, who in turn whispers the message to yet a fourth child and so on until the message has been whispered to the last child in the circle. By the time the message reaches its destination, the final child, it has undergone significant changes. Think of RNA as the mediator that ensures that the initial message is not distorted. RNA helps to facilitate our cell:cell communication by ensuring that the messages in our genes (our DNA) are accurately converted into the structural building blocks for our body (our proteins) in spite of the stresses, the toxins and the infectious diseases in our lives. Specific RNAs can help us to address proper cell: cell communication that is necessary to address multifactorial disease. RNA Based Support Knowledge is power. Armed with this knowledge and genetic profile analysis we can select precise natural RNA formulas that will aid in cell : cell communication to help to address the genetic susceptibilities that are involved in a variety of health conditions. (Stress, Health Foundation, Heart Support, Methylation Support, Nerve Calm, Mood S, Mood D, Mood Focus, Respiratory Support, Brain Support, CSF Support, Lipid Support ,Kidney Support, Healthy Microbial Balance, Organ Support, Bone Support and ProLongevity RNA NutriSwitch™ Formulas among others). For while we cannot change our genes, we can help to enhance the expression of these genes. DNA for testing RNA for balancing Relationship between specific genetic mutations and biochemical pathways and what we can do to address these mutations Specific Mutations of Interest CBS cystathionine beta synthase COMT catechol-O-methyltransferase MTHFR A1298C methylene tetrahydrofolate reductase MTHFR C677T methylene tetrahydrofolate reductase MS(MTR)A2576G methionine synthase MSR(MS_MTRR) A66G methionine synthase reductase NOS nitric oxide synthase SOD super oxide dismutase VDR vitamin D receptor Consequences of these mutations Increased Homocysteine Decreased Methylation Decreased BH4 Elevated Ammonia Homocysteine is elevated in the following pathological states: • • • • • • • • • Renal failure Thyroid dysfunction Heart transplantation Cardiovascular events Diabetes Neural tube defects Downs syndrome Alzheimer’s disease Autism Decreased BH4 is associated with the following: • • • • • • • Diabetes Atypical phenylketonuria (PKU) Decreased dopamine levels Decreased serotonin levels Hypertension Atherosclerosis Decreased NOS, endothelial dysfunction States associated with undermethylation • • • • • Cancer Aging Cardiovascular disease Neurological function Retroviral transmission Ammonia toxicity • Disorientation, “brain fog", confusion • Flapping tremors of extended arms • Hyperactive reflexes • Activation of N-methyl-D- aspartate receptors leading to glutamate excitotoxicity • Tremor of the hands • Paranoia, panic attacks • Memory loss • Hyperventilation (caused by respiratory alkalosis of high ammonia levels that stimulate the respiratory center; respiratory alkalosis is often associated with decreased CO2) • CNS toxicity affecting glial and nerve cells a, leading to altered CNS metabolism and function. AMMONIA AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 How do you know if you have any of these mutations? Testing for Mutations • Saliva tests • Blood tests • Both MTHFR mutations A1298C C677T Interpreting the Results • • • • A1298C+/A1298C+ A1298C-/A1298CA1298C+/A1298CA1298C-/A1298C+ homozygous no mutation heterozygous heterozygous Punnett Square A Punnett square is a chart which shows/predicts all possible gene combinations in a cross of parents (whose genes are known). Punnett squares are named for an English geneticist, Reginald Punnett. He discovered some basic principles of genetics, including sex linkage and sex determination. The standard way of working out what the possible offspring of two parents will be is the Punnett Square. Consider a single gene. Since each individual has one pair of each chromosome, they have two copies of each gene (one on each chromosome). A Punnett square is a simple graphical way of figuring out how the genes from each parent might combine to produce an offspring. The Punnett square duplicates the observation that the reproductive cells (eggs and sperm) get only half the normal number of chromosomes. When an egg is made, it receives one of each pair of chromosomes, not both. Likewise with sperm. Since eggs and sperm each carry only one of each chromosome instead of a pair of each, they carry only one copy of each gene instead of two. Thus a female who carries two different flavors (alleles) for a particular gene, produces some eggs reproductive cells that carry one flavor, and some eggs that carry the other. A male with two different alleles for the same gene likewise produces some sperm carrying one allele and some sperm carrying the other. A1288C + A1288C + A1288C + A1298C + A1288C + A1288C + A1288C + A1288C + A1288C + A1288C + A1288C + A1288C + A1288C - A1288C - A1288C - A1298C - A1288C – A1288C – A1288C - A1288C - A1288C – A1288C – A1288C - A1288C - A1288C - A1288C + A1288C + A1298C - A1288C – A1288C – A1288C + A1288C + A1288C – A1288C – A1288C + A1288C + A1288C + A1288C - A1288C + A1298C - A1288C + A1288C – A1288C - A1288C - A1288C + A1288C – A1288C + A1288C + Supplementation based on specific mutations Methylation Cycle Supplementation • ¼ Folapro • ¼ Intrinsic B12 • ¼ Nucleotides • Methylation Support RNA • TMG and /or phosphatidyl serine • Sublingual B12 and /or B12 injections COMT + + : hydroxy cobalamin COMT - -: methyl cobalamin Regardless of COMT status: cyano cobalamin (eyes) • Methionine SAMe for COMT - Methionine COMT + + • Optional methyl donors for COMT - - and COMT + MSM, TMG, DMG, curcumin, methyl B12, melatonin, FgF, caffeinated tea AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 COMT COMT is the enzyme that inactivates dopamine and norepinephrine by adding a methyl group to these compounds. • COMT has an allelic variation with high activity, which decreases dopamine • COMT has an allelic variation with low activity, leads to less of a decrease of dopamine COMT In the case of COMT the amino acid change is from a valine to a methionine. This is what is being tested for in the COMT genetic test. The labs are able to look at the DNA to determine which amino acid your version of COMT has. If you have the version with a methionine in it is written as COMT + meaning the genetic test is positive for the methionine version. If the result is COMT- it means that you do not have methionine in that spot of the enzyme and have valine there instead. Since the valine in that spot is considered the “norm” the methionine represents the variation, so it is + for a variation being present. The form of the COMT with the variation (the methionine in it at a particular location) is a less efficient form of the enzyme. When the methionine is present it does not do as good a job of breaking down the dopamine. So an individual with the COMT+ will not break dopamine down as easily. An individual with COMT-(with the valine in that spot) will break dopamine down more efficiently. The reason that we have two ++ or two - - or + - is that we all have two copies of the DNA for the COMT enzyme; one from each parent. Another way to represent COMT + + is as COMT met/met. Another way to represent COMT - - is as COMT val/val. COMT val/val - - • The dopamine pathway is tied to the folate and methionine cycles. • Individuals who are COMT - - will inactivate dopamine (and norepinephrine) more rapidly and as such will be depleting methyl groups from the methylation cycle in the process. Consider supplementation to help to maintain healthy dopamine levels. • Mood D (1/4 dropper once to twice a day) Mood Focus (1/8 to 1/4 dropper once a day) Quercetin supplementation • • S adenosyl homocysteine (SAH) acts to slow down the activity of COMT. As a result consider supplementation with SAMe. This will support methylation as well as generate SAH. SAH also is reported to have antiviral activity. • Individuals who are COMT - - tend to have a higher viral and metals load, and require higher doses of Metals RNA to facilitate detoxification. • Compounding mutation : MTHFR A1298C COMT met/met + + • Individuals who are COMT + + seem to have less of a viral and metal load, are more sensitive to supplements, recover language more easily (or never lost it), require a lower dose of the Metals RNAs for detoxification, and are more likely to exhibit "mood swing" type behaviors if you are not careful with food , supplementation, and also during detoxification. • Supplementation with quercetin, Mood D, Mood Focus is not advised. • Supplementation with additional methyl donors such as MSM, TMG, DMG, curcumin, methyl B12, melatonin, FgF, caffeinated tea is not advised. • Caution should be used with high dopamine content foods. High Dopamine Foods • • • • • • • • • • • • • • • • • • Alcoholic beverage (some, not all alcohol) Homemade yeast breads Crackers containing cheese Sour cream Bananas Red plums Avocados Figs Raisins Aged game Liver Canned meats Yeast extracts Commercial meat extracts Stored beef liver Chicken livers Salami Sausage • • • • • • • • • Aged cheese (including Blue, Boursalt, Brick, Brie, Camembert, Cheddar, Colby, Emmental, Gouda, Mozzarella, Parmesan, Provolone, Romano, Roquefort, and Stilton) Salted dried fish (herring, cod), pickled herring Italian broad beans Green bean pods Eggplant Yeast concentrates or products made with them Marmite Soup cubes Commercial gravies- anything with soy sauce, and an protein that has not been stored properly or has some degree of spoilage (i.e., all but those that have been freshly prepared). Vitamin D Receptor Environmental Medicine Amyotrophic Lateral Sclerosis, Lead, and Genetic Susceptibility: Polymorphisms in the -Aminolevulinic Acid Dehydratase and Vitamin D Receptor Genes Freya Kamel,1 David M. Umbach,1 Teresa A. Lehman,2 Lawrence P. Park,3 Theodore L. Munsat,4 Jeremy M. Shefner,5 Dale P. Sandler,1 Howard Hu,6 and Jack A. Taylor1 1National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; 2Bioserve Biotechnologies, Rockville, Maryland, USA; 3Westat, Durham, North Carolina, USA; 4New England Medical Center, Boston, Massachusetts, USA; 5SUNY Upstate Medical University, Syracuse, New York, USA 6Harvard Medical School and Harvard School of Public Health, Boston, Massachusetts, USA Abstract Previous studies have suggested that lead exposure may be associated with increased risk of amyotrophic lateral sclerosis (ALS). Polymorphisms in the genes for -aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR) may affect susceptibility to lead exposure. We used data from a case-control study conducted in New England from 1993 to 1996 to evaluate the relationship of ALS to polymorphisms in ALAD and VDR and the effect of these polymorphisms on the association of ALS with lead exposure. The ALAD 2 allele (177G to C; K59N) was associated with decreased lead levels in both patella and tibia, although not in blood, and with an imprecise increase in ALS risk [odds ratio (OR) = 1.9; 95% confidence interval (95% CI), 0.60-6.3]. We found a previously unreported polymorphism in ALAD at an Msp1 site in intron 2 (IVS2+299G>A) that was associated with decreased bone lead levels and with an imprecise decrease in ALS risk (OR = 0.35; 95% CI, 0.10-1.2). The VDR B allele was not associated with lead levels or ALS risk. Our ability to observe effects of genotype on associations of ALS with occupational exposure to lead or with blood or bone lead levels was limited. These findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure. Key words: -aminolevulinic acid dehydratase, amyotrophic lateral sclerosis, genetic susceptibility, lead, vitamin D receptor. Environ Health Perspect 111:1335-1339 (2003). doi:10.1289/ehp.6109 available via http://dx.doi.org/ [Online 1 April 2003] Vitamin D Receptor AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 VDR Mutations • • • • • • Vitamin D levels are closely tied to neurological conditions. Supplement with at least 1000 IU of supplemental vitamin D daily. Supplement with ¼ dropper of ProLongevity RNA daily. Vitamin D is also related to blood sugar regulation. Consider supplementation with Vitamin K1/K2 to help with potential blood sugar issues. The relationship between Vitamin D and insulin levels can also affect weight control as well as eating habits. Consider supplementation with : Ora pancreas chromium picolinate gymnema sylvestre Digestive enzymes containing pancreatic extract VDR Mutations • • • • Bsm Taq Fok Compensatory effect of lack of Bsm and Taq mutations • Relationship between elevated vitamin D and dopamine levels AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 Vitamin D and Dopamine Brain Res Mol Brain Res. 1996 Feb;36(1):193-6.Related Articles, Links Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells. Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK. Laboratory of Molecular Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA. We examined expression of the 1,25-dihydroxyvitamin D3 [1,25-(OH)2 D3] receptors in chromaffin cells of the adrenal medulla and the effects of 1,25(OH)2 D3 on expression of the tyrosine hydroxylase (TH) gene. Accumulation of 1,25(OH)2 D3 in the nuclei of adrenal medullary cells, but not in the adrenal cortex, was observed in mice intravenously injected with radioactively labeled hormone. 1,25(OH)2 D3 produced concentration-dependent increases in the TH mRNA levels in cultured bovine adrenal medullary cells (BAMC). The maximal increases (2-3-fold) occurred at 10(-8) M 1,25(OH)2 D3. Combined treatment with 1,25(OH)2 D3 and 20 microM nicotine had no additive effect on TH mRNA levels suggesting that transsynaptic (nicotinic) and vitamin D (hormonal) stimulation of TH gene expression are mediated through converging mechanisms. Induction of TH mRNA by 1,25(OH)2 D3 was not affected by calcium antagonist TMB-8. By increasing expression of the rate limiting enzyme in the catecholamine biosynthetic pathway, 1,25-(OH)2 D3 may participate in the regulation of catecholamine production in adrenal chromaffin cells. This regulation provides mechanisms through which 1,25(OH)2 D3 may control response and adaptation to stress. AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 The magnitude of the genetic association is substantial with those in the "TT" group having a 50-60% reduction in risk compared with the "tt" group with heterozygotes in between. TT = Bsm/Taq - The Taq-1 polymorphism is located within 1.1 kb 3' of the polymorphic Bsm-1 site and is in strong linkage disequilibrium with the previously reported Bsm-1 polymorphism such that there is up to 97% concordance of genotype. Because of this strong linkage and the presence of an internal control in the Taq1 RFLP, only the Taq-1 RFLP was determined in the present study population. Presence (t) and absence (T) of the polymorphic Taq-I restriction endonuclease site are in linkage with the absence (B) and presence (b) respectively of the polymorphic Bsm-I site. • High Vitamin D is associated with lower rates of osteoarthritis • Previous study showed that the absence of the Taq and Bsm sites were associated with lower levels of osteoarthritis • Implies that lack of Taq and Bsm lead to higher levels of Vitamin D • High Vitamin D increases dopamine • Fits with observation that Bsm - - and Taq - may mitigate other mutations in autism severity • Fits with observation that Bsm - - and Taq - COMT + + children are the most sensitive to dopamine and methyl groups MTHFR A1298C • The A1298C mutation has been mapped to the SAMe regulatory region of the gene. • Mutations in the A1298C do not lead to increased levels of homocysteine; as such it has been felt that this mutation may not be of serious consequence. • Literature suggests that the MTHFR enzyme can drive the reverse reaction leading to formation of BH4. • Dr. Yasko has suggested that the A1289C mutation is associated with a defect in the reverse reaction leading to the formation of BH4. • The A1298C mutation would then be associated with an inability to convert BH2 to BH4. This would impact levels of dopamine, serotonin, norepinephrine , and phenylalanine. • The availability of BH4 helps to determine whether nitric oxide, peroxy nitrite or super oxide are formed as a function of the urea cycle; two molecules of BH4 are required for formation of nitric oxide, one molecule of BH4 leads to the formation of peroxy nitrite and the absence of BH4 leads to super oxide formation. AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 MTHFR A1298C ++ • MTHFR gene with the A1298C mutation may decrease the formation of BH4. • This mutation impacts dopamine levels as well as the levels of serotonin and the urea cycle. • Supplementation for optimal methylation cycle function should be followed. • Methylation cycle supplementation should be adapted to the relevant COMT status. • Consider supplementation to help to maintain healthy dopamine and serotonin levels. The specific supplementation utilized should be dependent on the COMT status. • Compounding mutation : CBS C699T + + • Dr. Yasko has found that more severe autistic children have A1289C + +,CBS + + COMT - -. High Dopamine Foods • • • • • • • • • • • • • • • • • • Alcoholic beverage (some, not all alcohol) Homemade yeast breads Crackers containing cheese Sour cream Bananas Red plums Avocados Figs Raisins Aged game Liver Canned meats Yeast extracts Commercial meat extracts Stored beef liver Chicken livers Salami Sausage • • • • • • • • • Aged cheese (including Blue, Boursalt, Brick, Brie, Camembert, Cheddar, Colby, Emmental, Gouda, Mozzarella, Parmesan, Provolone, Romano, Roquefort, and Stilton) Salted dried fish (herring, cod), pickled herring Italian broad beans Green bean pods Eggplant Yeast concentrates or products made with them Marmite Soup cubes Commercial gravies- anything with soy sauce, and an protein that has not been stored properly or has some degree of spoilage (i.e., all but those that have been freshly prepared). High Tryptophan Foods may increase Serotonin • • • • • • • Spirulina (seaweed) Soy Nuts Chicken Liver Pumpkin Seeds Turkey Chicken Tofu Watermelon Seeds Almonds Peanuts Brewer’s Yeast Cottage Cheese Milk Yoghurt AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 Brain Res. 2002 May 10;935(1-2):47-58 Glutathione depletion in nigrostriatal slice cultures: GABA loss, dopamine resistance and protection by the tetrahydrobiopterin precursor sepiapterin. Gramsbergen JB, Sandberg M, Moller Dall A, Kornblit B, Zimmer J. Anatomy and Neurobiology, Institute of Medical Biology, SDU-Odense University, Winsloewparken 21, DK-5000 C Odense, Denmark. jbg@imbmed.ou.dk Dopaminergic neurons in culture are preferentially resistant to the toxicity of glutathione (GSH) depletion. This effect may be due to high intrinsic levels of tetrahydrobiopterin (BH(4)). Here we studied the effects of manipulating GSH and/or BH(4) levels on selective neurotoxicity in organotypic nigrostriatal slice cultures. Following treatments with L-buthionine sulfoximine (BSO, 10-100 microM, 2 days exposure, 2 days recovery), either alone or in combination with the BH(4) precursor L-sepiapterin (SEP, 20 microM), or the BH(4) synthesis inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP, 5 mM), toxic effects were assessed by HPLC analysis of medium and tissues, cellular propidium iodide (PI) uptake, lactate dehydrogenase (LDH) efflux, as well as stereological counting of tyrosinehydroxylase (TH) positive cells. Thirty micromolar BSO produced 91% GSH and 81% GABA depletion and general cell death, but no significant effect on medium homovanillic acid (HVA) or tissue dopamine (DA) levels. SEP prevented or delayed GABA depletion, PI uptake and LDH efflux by BSO, whereas DAHP in combination with BSO caused (almost) complete loss of medium HVA, tissue DA and TH positive cells. We suggest that under pathological conditions with reduced GSH, impaired synthesis of BH(4) may accelerate nigral cell loss, whereas increasing intracellular BH(4) may provide protection to both DA and GABA neurons. Brain Res. 2002 May 10;935(1-2):47-58 J Neurochem. 2000 Jun;74(6):2305-14. Preferential resistance of dopaminergic neurons to the toxicity of glutathione depletion is independent of cellular glutathione peroxidase and is mediated by tetrahydrobiopterin. Nakamura K, Wright DA, Wiatr T, Kowlessur D, Milstien S, Lei XG, Kang UJ. Department of Neurology, University of Chicago, IL 60637, USA. Depletion of glutathione in the substantia nigra is one of the earliest changes observed in Parkinson's disease (PD) and could initiate dopaminergic neuronal degeneration. Nevertheless, experimental glutathione depletion does not result in preferential toxicity to dopaminergic neurons either in vivo or in vitro. Moreover, dopaminergic neurons in culture are preferentially resistant to the toxicity of glutathione depletion, possibly owing to differences in cellular glutathione peroxidase (GPx1) function. However, mesencephalic cultures from GPx1-knockout and wild-type mice were equally susceptible to the toxicity of glutathione depletion, indicating that glutathione also has GPx1independent functions in neuronal survival. In addition, dopaminergic neurons were more resistant to the toxicity of both glutathione depletion and treatment with peroxides than nondopaminergic neurons regardless of their GPx1 status. To explain this enhanced antioxidant capacity, we hypothesized that tetrahydrobiopterin (BH(4)) may function as an antioxidant in dopaminergic neurons. In agreement, inhibition of BH(4) synthesis increased the susceptibility of dopaminergic neurons to the toxicity of glutathione depletion, whereas increasing BH(4) levels completely protected nondopaminergic neurons against it. Our results suggest that BH(4) functions as a complementary antioxidant to the glutathione/glutathione peroxidase system and that changes in BH(4) levels may contribute to the pathogenesis of PD. MTHFR COMT A1298C val/val ++ -- • MTHFR gene with the A1298C mutation may decrease the formation of BH4. • • This mutation impact dopamine levels as well as the levels of serotonin and the urea cycle. Supplementation for optimal methylation cycle function should be followed. • Methylation cycle supplementation should be adapted to the relevant COMT status. • Consider supplementation to help to maintain healthy dopamine and serotonin levels. The use of Mood S, Mood D and Mood Focus may put less of a drain on limited supplies of BH4 so that there is sufficient BH4 to drive the urea cycle. Mood S (1/4 dropper once to twice a day) Mood D (1/4 dropper once to twice a day) Mood Focus (1/8 to 1/4 dropper once a day) • Compounding mutation : CBS + + • Dr. Yasko has found that more severe autistic children have A1289C + +,CBS + + COMT - - AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 MTHFR A1298C COMT met/met + + • • • • • • • • MTHFR gene with the A1298C mutation may decrease the formation of BH4. This may not impact dopamine levels as severely as a result of the COMT mutation which may compensate in terms of dopamine levels. It may be prudent to add Mood S to help to support healthy serotonin levels. Between the use of Mood S and the presence of the COMT mutations it may put less of a drain on limited supplies of BH4 so that there is sufficient BH4 to drive the urea cycle. Individuals who are COMT + + seem to have less of a viral and metal load, are more sensitive to supplements, recover language more easily (or never lost it), require a lower dose of the Metals RNAs for detoxification, and are more likely to exhibit "mood swing" type behaviors if you are not careful with food , supplementation, and also during detoxification. Supplementation for optimal methylation cycle function should be followed. Methylation cycle supplementation should be adapted to the relevant COMT status. Compounding mutation : CBS A699T + + AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 MTHFR • • • • C677T ++ C677T mutation leads to less efficient activity of the enzyme through the methionine and folate pathways. The body is less able to make 5 methyl folate. The addition of Folapro as well as other methylation cycle supplementation should help to compensate for this mutation. Supplementation for optimal methylation cycle function should be followed. Methylation cycle supplementation should be adapted to the relevant COMT status. • The C677T mutation had been associated with an increased risk of heart disease • Compounding mutation : MSR (MS__MTRR) A66G Arch. Neurol. April 2005 • Subjects with the highest folate intake had twice the rate of mental decline over six years as those with the lowest folate intake. • Elevated homocysteine and the relationship to Alzheimer’s • Screening for the ability to use plain folate • Implication for C677T mutations in the population at risk for Alzheimer’s Dietary Folate and Vitamin B12 Intake and Cognitive Decline Among Community-Dwelling Older Persons Martha Clare Morris, ScD; Denis A. Evans, MD; Julia L. Bienias, ScD; Christine C. Tangney, PhD; Liesi E. Hebert, ScD; Paul A. Scherr, PhD, ScD; Julie A. Schneider, MD Arch Neurol. 2005;62:641-645. Background Deficiencies in folate and vitamin B12 have been associated with neurodegenerative disease. Objective To examine the association between rates of age-related cognitive change and dietary intakes of folate and vitamin B12. Design Prospective study performed from 1993 to 2002. Setting Geographically defined biracial community in Chicago, Ill. Participants A total of 3718 residents, 65 years and older, who completed 2 to 3 cognitive assessments and a food frequency questionnaire. Main Outcome Measure Change in cognitive function measured at baseline and 3-year and 6-year follow-ups, using the average z score of 4 tests: the East Boston Tests of immediate and delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test. Results High folate intake was associated with a faster rate of cognitive decline in mixed models adjusted for multiple risk factors. The rate of cognitive decline among persons in the top fifth of total folate intake (median, 742 µg/d) was more than twice that of those in the lowest fifth of intake (median, 186 µg/d), a statistically significant difference of 0.02 standardized unit per year (P = .002). A faster rate of cognitive decline was also associated with high folate intake from food (P for trend = .04) and with folate vitamin supplementation of more than 400 µg/d compared with nonusers ( = –.03, P<.001). High total B12 intake was associated with slower cognitive decline only among the oldest participants. Conclusions High intake of folate may be associated with cognitive decline in older persons. These unexpected findings call for further study of the cognitive implications of high levels of dietary folate in older populations. Author Affiliations: Rush Institute for Healthy Aging (Drs Morris, Evans, Bienias, and Hebert), Departments of Internal Medicine (Drs Morris, Evans, Bienias, and Hebert), Preventive Medicine (Dr Morris), and Clinical Nutrition (Dr Tangney), and Rush Alzheimer’s Disease Center (Dr Schneider), Rush University Medical Center, Chicago, Ill; and Division of Adult and Community Health, Centers for Disease Control and Prevention, Atlanta, Ga (Dr Scherr). AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 MS (MTR) A2576G • This mutation is reported to increase the activity of the methionine synthase enzyme. • While this may result in lower homocysteine levels, it may also deplete intermediates from the methylation cycle. • • Supplementation for optimal methylation cycle function should be followed. Methylation cycle supplementation should be adapted to the relevant COMT status. • This mutation may also be correlated with an elevated risk for Down’s Syndrome. • The effect of this mutation may be compounded by a CBS mutation which also acts to deplete intermediates of the methylation cycle. • Compounding mutation : CBS C699T + + MSR(MS_ _MTRR) A66G + + • • • • • The function of MSR is to regenerate B12 for the MS to utilize. This mutation reduces the ability of MSR to regenerate methylcobolamin. Supplementation for optimal methylation cycle function should be followed. Methylation cycle supplementation should be adapted to the relevant COMT status. Supplementation with small amounts of methyl B12 and SAMe should be considered even for individuals who are COMT + +. • Supplement with additional with B12 beyond basic levels COMT + + : hydroxy cobalamin COMT - -: methyl cobalamin Regardless of COMT status: cyano cobalamin (eyes) • There is a second pathway to generate methionine via the BHMT enzyme that will bypass the MSR mutation. This pathway uses phosphatidyl serine and /or TMG as donors for the reaction. • This mutation can an lead to elevated homocysteine levels • Compounding mutation: MTHFR C677T B12 • Low levels of B12 are associated with lower bone density • Risk of breaking a hip after a fall was 80% lower in those supplemented with adequate levels of vitamin B12 and folate • Pernicious anemia • Energy AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 CBS C699T ++ • The C699T mutation in the CBS enzyme causes this enzyme to work at a higher efficiency. This will drain the homocysteine from the methylation cycle so that we further deplete methyl groups and methyl donors in this pathway. • Methionine, SAMe and carnitine aid in addressing excess ammonia; however CBS C699T and other methylation cycle mutations deplete this pathway making it difficult to maintain adequate levels of methionine and SAMe. SAMe is necessary for carnitine synthesis. • Consider supplementing with SAMe, methionine, carnitine, charcoal or bentonite to decrease ammonia. • Ammonia intoxication can be reduced by restricting the growth of ammonia-producing bacteria and limiting the amount of protein in the diet. • Suggest keeping protein in the diet to a minimum. • Consider Ammonia Support RNA • Recommend against the use of high levels of taurine or additional sulfur donors (broccoli etc) as it may create problems with excess sulfur groups. • Too much added glutathione can be a problem due to sulfur excess as a result of the CBS mutation. • Compounding mutation : MTHFR A1298C AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 Specimen Marker Before Low Protein/Ammonia Support RNA After Low Protein/Ammonia Support RNA Reference Range Ammonia Level 52,500 15,000 7,000-36,000uM Taurine 3610 880 200-1000 Cysteine 35 20 15-54 Arginine 6.3 33 5-35 Homocysteine 1.6 2.5 <3 Sarcosine 7.9 5 <5 Beta alanine 160 28 <10 Carnosine 320 25 <100 GABA <dl 2.5 <5 Ornithine 3.2 15 1.5-20 Science News April 23, 2005 Inducing a “topor like” state with hydrogen sulfide gas. The gas competes with oxygen in mitochondria, slowing the metabolic activity. Topor is an extreme state of metabolic slowdown in which the heart rate drops, breathing slows and body temperature plunges. AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 CBS C699T - - • If there is no mutation to up regulate the CBS enzyme the intermediates in the methionine cycle should not be depleted to the extent that they are with a CBS C699 T mutation. • There should not be an excess of sulfur containing groups as a result of excessive conversion of homocysteine to cysteine and taurine. • Sulfur donors should be well tolerated. • The lack of the CBS up regulation can lead to elevated homocysteine levels. • Supplementation for optimal methylation cycle function should be followed. • Forward mutations in the MTHFR, C677T can lead to elevated homocysteine levels. • Compounding mutations : MTHFR C677T, MSR(MS__MTRR) A66G AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 Combinations of Genetic Variations November ACAM Meeting CBS MTHFR C699T + + A1298C + + • The C699T mutation in the CBS enzyme causes this enzyme to work at a higher efficiency. This will drain the homocysteine from the methylation cycle so that we further deplete methyl groups and methyl donors in this pathway. The conversion of homocysteine via this enzyme also generates ammonia. • Dr. Yasko believes that individuals with the A1298C mutation have problems with the reverse reaction through the MTHFR which drives the reaction of BH2 to BH4 . This impacts the levels of serotonin, dopamine, norepinephrine and the urea cycle (getting rid of ammonia) • Limited BH4(due to A1298C) will create issues with the urea cycle and the ability to use this cycle properly to eliminate ammonia in a less toxic fashion. CBS MTHFR • C699T + + A1298C + + The amount of BH4 also plays a direct role in the urea cycle With no BH4 the cycle will still function, however super oxide will be generated which causes oxidative damage, neuronal damage and microglial activation. With one molecule of BH4 for each turn of the urea cycle the damaging peroxy nitrite will be produced. It requires two molecules of BH4 in order to make citrulline and nitric oxide (NO) properly • The depletion of BH4 due to excess ammonia generated by the CBS C699T mutation can be partially compensated by a COMT++ status. With COMT++ it will slow the breakdown of dopamine and so it will require less BH4 to make more dopamine and leave more of the limited BH4 to make serotonin and convert arginine to citrulline in the urea cycle. This may be why children who are COMT-- and A1298C ++ may have the greater difficulties. CBS MTHFR C699T + + A1298C + + • Methionine, SAMe and carnitine aid in addressing excess ammonia; however CBS C699T and other methylation cycle mutations deplete this pathway making it difficult to maintain adequate levels of methionine and SAMe. SAMe is necessary for carnitine synthesis. • SAH which is an intermediate in this pathway helps to inhibit COMT so that if you are COMT-- but can make sufficient SAH it will help to slow down the degradation of dopamine and help to compensate for the COMT- -. • BH4 reaction is inhibited by aluminum. A1298C/ CBS/ Protein • Increased ammonia puts strain on the urea cycle. • Decreases BH4. • May either generate excessive Nitric Oxide or not enough NO. • Also generates peroxy nitrite and superoxide. Excess superoxide in turn affects SOD. The urea cycle is an endergonic process that ultimately requires the hydrolysis of 3 ATP's for each molecule of urea produced In the first reaction, which occurs in mitochondria, bicarbonate (HCO3¯) is combined with NH4+ to form carbamoyl phosphate http://www.lander.edu/flux/301_aminoacid_catabolism.htm Functions of Nitric Oxide • • • • NO inhibits platelet aggregation, keeping inappropriate clotting from interfering with blood flow. Release of NO around the glomeruli of the kidneys increases blood flow through them thus increasing the rate of filtration and urine formation. The wavelike motions of the gastrointestinal tract are aided by the relaxing effect of NO on the smooth muscle in its walls. NO affects secretion from several endocrine glands. • • • • • • • • • it stimulates the release of Gonadotropin-releasing hormone (GnRH) from the hypothalamus; the release of pancreatic amylase from the exocrine portion of the pancreas; the release of adrenaline from the adrenal medulla. Some motor neurons of the parasympathetic branch of the autonomic nervous system release NO as their neurotransmitter. NO is released by neurons in the CA1 region of the hippocampus and stimulates the NMDA receptors there that are responsible for long-term potentiation (LTP) — a type of memory (and learning). Mice whose genes for nNOS have been knocked out are healthy but display abnormal behavior, e.g., they kill other males and try to mate with nonreceptive females. Nitric oxide plays an integral role in the airway; nonadrenergic, noncholinergic (NANC) parasympathetic relaxant nerves are the primary relaxant nerves innervating airway smooth muscle. Studies indicate that muscarinic cholinergic inhibition of beta-adrenergic cardiac responses may be modulated in part by nitric oxide (NO) Consequences of Excessive Nitric Oxide • • • • • • • Leaky blood brain barrier Neuro degeneration Demyelination Degradation of mucin (protective for the gut) Increases intestinal permeability Inhibits gall bladder contraction Mediates slow transit constipation McGinnis, W. Oxidative Stress in Autism, Alternative Therapies 10(6), 2004. AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 Glutathione S Transferase Glutathione conjugation: Glutathione is a tripeptide (gglutamylcyteinylglycine, with the amino acid residues color coded in the structures below). It is used in cells as a recyclable anti-oxidant as well as a conjugating agent. When used in conjugation it is initially conjugated by a glutathione-Stransferase, or sometimes as a simple chemical reaction. Generally the conjugation occurs as a nucleophilic attack by the -SH group on a reactive electrophilic center. Conjugation is often followed by metabolic cleavage of the peptide to leave only the cysteinyl residue, which may then be acetylated to give a mercapturic acid. Of course not all glutathione derivatives are further metabolized, some may be excreted as is. However, if the derivative is excreted via the bile, it may be metabolized by the gut fauna and the toxin may be reabsorbed. Example: 1. Glutathione S-transferase: 2. g-glutamyltranspeptidase: 3. cysteinyl glycinase: 4. N-acetyl transferase: www.humboldt.edu/.../C451LecNotesar10.html GSTM1 GSTP1 GSTT1 • GST enzymes bind glutathione to products of detoxification reactions to aid in excretion from the body. • Mutations in the GST enzyme pathway may be liberally supplemented with sulfur donors as well as with glutathione, except for individuals with CBS C699T + + mutations. Glutathione supplementation would include the use of topical glutathione, oral glutathione, IV glutathione could be considered with the addition of NADH. Also supplementation with NAC (500mg per day), vitamin C with rose hips (500mg two to three times per day), vitamin E with mixed tocopherols, and selenium. These supplements will help to maintain and regenerate healthy glutathione levels. Consider Thione sublingual glutathione. Consider LipoFlow glutathione which is encapsulated in liposomes to enhance delivery. Consider supplementation with sulfur donors, these would include taurine, broccoli extract, glucosamine and/or chondroitin. • • • • • • • • High levels of cysteine lead to the formation of taurine rather than glutathione. Reduced levels of cysteine favor the formation of glutathione CBS mutations lead to decreased levels of glutathione. Yet may create greater sensitivity to glutathione and other sulfur containing compounds. • Complicating mutation : CBS C699T + + AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 SOD Superoxide dismutases are an ubiquitous family of enzymes that function to efficiently catalyze the dismutation of superoxide anions. Three unique and highly compartmentalized mammalian superoxide dismutases have been biochemically and molecularly characterized to date. SOD1, or CuZn-SOD (EC 1.15.1.1), was the first enzyme to be characterized and is a copper and zinc-containing homodimer that is found almost exclusively in intracellular cytoplasmic spaces. SOD2, or MnSOD (EC 1.15.1.1), exists as a tetramer and is initially synthesized containing a leader peptide, which targets this manganese-containing enzyme exclusively to the mitochondrial spaces. SOD3, or EC-SOD (EC 1.15.1.1), is the most recently characterized SOD, exists as a copper and zinc-containing tetramer, and is synthesized containing a signal peptide that directs this enzyme exclusively to extracellular spaces. What role(s) these SODs play in both normal and disease states is only slowly beginning to be understood. A molecular understanding of each of these genes has proven useful toward the deciphering of their biological roles. Free Radic Biol Med. 2002 Aug 1;33(3):337-49. Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. SOD Reaction http://cropsoil.psu.edu/Courses/AGRO518/IMG00024.GIF SOD • • • • • Free oxygen radicals are extremely reactive and can cause damage to the body. The oxygen free radical is also known as super oxide radical. Super oxide can be converted to even more damaging radicals by a chain reaction. Radicals are highly reactive and unstable, and will attack any molecule in the body. SOD enzymes scavenge and destroy free radicals in the body, including super oxide radicals. Organ or tissue damage can occur whenever production of free radicals exceeds that of free radical scavenger enzymes such as SOD. There are several types of SOD: SOD1 or CuZnSOD = Intracellular (cytosolic) SOD SOD2 or MnSOD = Mitochondrial SOD SOD3 or EcSOD = Extracellular SOD • Complicating mutation : CBS C699T + + AMMONIA “When the need is for energy and not for cysteine, homocysteine is metabolized to Alpha KG, NH3 and H2S.” Textbook of Biochemistry with Clinical Correlations ,Devlin 2002 Fragile X • • • • DNA methylation FMRP is an RNA binding protein Excessive glutamate Decreased pruning Glucose 6 Phopshate Dehydrogenase (G6PD) Labcorp Number001917 CPT82955; 85041 Synonyms G6PDH; G6PD, Quant, Blood and RBC; G6PD, Quantitative, Blood Test Includes Quantitative G6PD; red blood cell count (RBC) The Hexose Monophosphate Shunt G6PDH and Blood Sugar • Hexokinase converts glucose into a form that is trapped in the cells. • Hexokinases are inhibited by Glucose 6 phosphate dehydrogenase accumulation Inhibitory effects of various sulfur compounds on the activity of bovine erythrocyte enzymes. Khan AA, Schuler MM, Coppock RW. J Toxicol Environ Health. 1987;22(4):481-90 Studies were conducted to assess the in vitro effects of selected sulfur compounds on the activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GSHPX), and glucose6-phosphate dehydrogenase (G6PDH) in hemolyzates of bovine erythrocytes. All sulfur compounds produced concentration-dependent inhibition in the activities of these enzymes, but their effects on each enzyme were different. SOD and catalase activities were most sensitive to sulfide (S2-), followed by sulfite (SO3(2-)) and sulfate (SO4(2-)). GSHPX activity was most sensitive to SO3(2-), followed by S2-, cysteine and SO4(2-). The activity of G6PDH, however, was maximally inhibited by reduced glutathione (GSH), followed by SO3(2-) and SO4(2-); S2- was inhibitory only at high concentrations. Dialysis of the S2- and SO3(2-)-inhibited enzymes resulted in complete or partial reversal of inhibitory effects. The biochemical significance of these effects in relation to erythrocyte physiology is discussed. The effect of N,N'-p-phenylenedimaleimide (PMD) on deoxygenation-induced K loss in sickle erythrocytes. Wall SN, Berkowitz LR. J Toxicol Environ Health. 1987;22(4):481-90 Am J Med Sci. 1987 Aug;294(2):105-9 A variety of thiol reactive agents have been found to have antisickling properties thought to be due to the ability of these drugs to bind to hemoglobin, resulting in increased hemoglobin-oxygen affinity. Because thiol reactive agents also influence K movements in red cells and deoxygenation leads to K loss and Na gain in sickle erythrocytes, the authors investigated the possibility that deoxygenation-induced K loss could be influenced by thiol agents, independent of an effect on hemoglobin-oxygen affinity. Experiments were performed with the thiol crosslinking agent N,N'-pphenylenedimaleimide (PMD). The authors found that PMD inhibited deoxygenation-induced K loss in sickle erythrocytes. This effect was not due to sickling inhibition as PMD-treated cells gained Na with deoxygenation, nor could the effect be explained by monofunctional PMD binding to membrane sulfhydryl groups, as a monofunctional analogue of PMD was not able to retard deoxygenation-induced K loss. These findings support a role for membrane sulfhydryl groups in deoxygenation-induced K movements in sickle red cells and suggest that this K loss may be prevented by crosslinking of certain membrane sulfhydryl groups. G6PD deficiency is caused by one copy of a defective G6PD gene in males or two copies of a defective G6PD gene in females. Hemolytic anemic attacks can be caused by oxidants, infection, and or by eating fava beans. Sudden attacks of G6PD deficiency can be caused by any serious illness and certain medicines such as: Medicines for the treatment of malaria: Chloroquine, Primaquine, Pamaquine, Pentaquine, Plasmoquine, Quinine, Quinocide Medicines for fever and pain: Acetanilid, Acetylsalicylic acid, Aminopyrine, Antipyrine Sulphonamides: Sulphanilamide, Sulphacetamide, Sulphapyridine, Sulphamethoxypyradizine Sulphones: Sulphoxone, Thiazolsulfone, Diaminodiphenyl Sulphone Nitrofurans: Nitrofurantonin, Furazolidone, Nitrofurazone Others: Phenylhydrazine, Acetylphenylhydrazine, Probenecid, Dimercaprol(DMSA), Methylene blue, Naphthalene, Vitamin K, Aminosalicylic acid, Chloramphenicol, Vitamin C (only in very high doses), Neosalvarsan Glucose-6-phosphate dehydrogenase deficiency promotes endothelial oxidant stress and decreases endothelial nitric oxide bioavailability JANE A. LEOPOLD2, ANDRE CAP, ANNE W. SCRIBNER, ROBERT C. STANTON* and JOSEPH LOSCALZO Deficient G6PD activity is associated with a reduction in NADPH stores, which in turn may influence levels of BH4. Impact of G6PDH Deficiency • • • • • • • • Decreased CO2 Glucose imbalances Increased AGE (advanced glucosyl end products) Decreased NADPH decreased BH4 Decreased reduced glutathione Decreased sugars for ATP,CoA,NAD,FAD, DNA, RNA Decreased Nitric Oxide availability Increased pyruvate Factors Affecting G6PDH Levels • • • • • • • • • • • • • Thyroid hormones increase the level High carbohydrate diets increase the level Insulin increases the level (relationship to vitamin D) Adrenal support increases the level EGF increases the level Estrogen increases the level PDGF increases the level Fatty acids decrease the level Cortisol decreases the level Copper decreases the level High vitamin C may be an issue High dose of vitamin K3 (synthetic menadione) may be an issue DHEA inhibits G6PDH activity Additional Resources • Glutamate and Gaba – Neurological Inflammation • Virus, Metals, Methylation – Austin Conference, November 2004 – Phoenix Conference, April 2005 • Factors Contributing to Autism – Putting It All Together Parents Weekend – Boston Conference, August 2004 • Genetics of Autism – Phoenix Conference, April 2005 – Personalized Medicine DVD/ Implications of Genetic Testing Book • RNA – Boston Conference, August 2004 – Phoenix Conference, April 2005 www.holistichealth.com www.holisticheal.com www.autismanswer.com Parents chatroom www.longevityplus-rna.com
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