Patients with MTHFR and methylation issues require a unique approach. The standard products on the market may not be suitable for those with specific issues and therefore a more targeted programme is required. The ability to split your B vitamins is desirable as each patient will have a different need and this allows you to tailor to the individual patient. What is methylation? Methylation or one carbon metabolism is a network of interrelated biochemical pathways for reduction or oxidation and transfer to other compounds. This allows the transfer of a methyl group (one carbon and three hydrogen atoms) onto amino acids, proteins, enzymes and DNA in every cell and tissue of the body. This regulates healing, produces energy, genetic expression of DNA, synthesises neurotransmitters, liver detoxification, immunity and hormonal clearance. So disturbances in this methylation pathway can have significant and widespread effects on many body systems. The key pathways are the folate pathway (of which the MTHFR gene is a crucial final step), the methionine pathway which plays a major role in methyl group metabolism as it allows the recycling of homocysteine back to methionine and elimination via the CBS (Cystathione beta synthase pathway). The methionine synthase enzyme contains a cobalamin cofactor 2 which ensures that with the help of Vitamin B12 the methyl group is transferred to homocysteine. Methionine, which is regenerated from homocysteine is then converted to S-adenosylmethionine (AdoMET). AdoMet then donates the methyl group it obtained from 5- MTHF to over 80 biological methylation reactions, including the methylation of DNA, RNA, proteins, lipids and lipoproteins. The key methyltransferases are the enzyme groups that benefit from this donation of methyl’s by AdoMET. What is MTHFR? MTHFR is a gene, which produces the MTHFR (methylenetetrahydrofolate reductase) enzyme and is considered a key enzyme in one-carbon metabolism, because it catalyses the irreversible conversion of 5,10-methylene THF to 5-methyl tetrahydrofolate.1 5-MTHF is our active folate that is then used in the methylation cycle. Folate Metabolism http://www.aacc.org/publications/cln/2011/january/Pages/FolateMetabolismFigure.aspx What happens if MTHFR activity is reduced? 1. 5-MTHF levels go down 2. Transmethylation cycle slows 3. All tissues except liver and kidney show effects of decreased methylation which leads to: - Decreased neurotransmitter production - Deficiency in glutathione 4. BHMT becomes depleted in choline which causes: homocysteine levels to rise methylation in the liver and kidneys decrease phosphatidylcholine production drops causing cell membrane and myelin instability This may then have affects for the following conditions: Diabetes Chemical sensitivity Cancer Congenital Heart defects Pulmonary embolisms Fibromyalgia Cleft palate Chronic fatigue syndrome Spina Bifida Depression Autism Alcoholism Parkinson’s Disease Addictive behaviours Neural tube defects Insomnia Cardiovascular disease – Downs syndrome atherosclerosis, elevated cholesterol, Autism hypertension, fat metabolism issues Chronic viral infection Immune deficiency Thyroid dysfunction ADD/ADHD Neuropathy MS Recurrent miscarriage Alzheimer’s Infertility Anxiety Schizophrenia Bipolar Allergies References 1. Selhub.J Homocysteine metabolism. Annu.Rev.Nutr. 19,217,1999 2. Weissbach. H and Taylor RT. Roles of Vitamin B12 and folic acid in methionine synthesis. Vitam. Horm. 28, 415, 1970. 3.Robinson K, Mayer EL, et al. Hyperhomocysteinemia and low pyridoxal phosphate: common and independent reversible risk factors for coronary artery disease. Circulation. 1995; 92:2825-2830. 4. Homocysteine and Risk of Ischemic Heart Disease and Stroke A Meta-analysis Homocysteine Studies Collaboration. JAMA. 2002;288(16):2015-2022. doi:10.1001/jama.288.16.20 5. Tungtrongchitr R, Pongpaew P, Prayurahong B, et al: Vitamin B12, folic acid and haematological status of 132 Thai vegetarians. Int J Vitam Nutr Res 1993; 63:201-207 Starter B & Methylation Support Specific Indication: Step 1 in methylation support. Initial support for people with the MTHFR gene mutation to aid, assist in or help support as a cofactor for key enzymes in the methylation cycle (Figure 1). Pharmaceutical Effects: Starter B contains six B vitamins without Vitamin B12 or folate. Clinical Benefits: The B vitamins all act as cofactors in the methylation cycle to support critical enzymes integral to the pathway. Thiamin (B1) and Pyridoxine (B6) are confirmed by human clinical trials to work together to cause a decrease in DNA glycation. 1-3Human studies show that the effect of Thiamin decreasing DNA glycation results in higher levels of methylation.2,3 Riboflavin (B2) acts as a cofactor for folate and so increases methylation. It is the limiting nutrient for pyridoxine folate and B12 metabolism.2,3,4 It can also assist niacin in reducing excessive DNA methylation.2 It is the cofactor for the MTHFR gene. Niacin (nicotinamide, B3) and its derivative nicotinamide are dietary precursors of nicotinamide adenine dinucleotide (NAD). NAD functions in oxidation-reduction (redox) reactions and non-redox reactions. 11 NAD is an important cofactor for MTRR (methionine synthase reductase) enzyme. http://lpi.oregonstate.edu/mic/vitamins/vitamin-B6 Figure 1. B vitamins & step 1 in methylation support & one-carbon metabolism. Pantothenic acid (B5) is confirmed by human clinical trials to improve the nutritional and metabolic status of the genome including DNA methylation,16,17 particularly for mental health in adults and psychology in children. 18,19,20 Pyridoxine (B6) is confirmed by human clinical trials to increase DNA methylation levels and work together with riboflavin, folate, and B12. 21,22Deficiency of Pyridoxine in animals results in reduction of DNA methylation. 23,24 B6 is an important cofactor for the CBS pathway. Biotin (B7) is confirmed by human clinical trials to be related to folate in its DNA methylation functions16,25. It works with other vitamins, such as pantothenic acid, riboflavin, niacin, pyridoxine, folate and B12, to play essential roles in maintaining mitochondrial functions including DNA methylation.2 All doses are safe according to the Australian RDI and the U. S. DRI. References 1Polizzi FC, Andican G, Çetin E, Civelek S, Yumuk V, Burçak G. Increased DNA-glycation in type 2 diabetic patients: the effect of thiamine and pyridoxine therapy. Experimental and clinical endocrinology & diabetes, June 2012, 120(6), 329-34. PubMed PMID: 22231921 2 Schupp N, Dette EM, Schmid U, Bahner U, Winkler M, Heidland A, Stopper H. Benfotiamine reduces genomic damage in peripheral lymphocytes of hemodialysis patients. Naunyn-Schmiedeberg's archives of pharmacology, September 2008, 378(3), 283-91. PubMed PMID: 18509620 3 Schupp N, Schmid U, Heidland A, Stopper H. New approaches for the treatment of genomic damage in end-stage renal disease. Journal of renal nutrition, January 2008, 18(1), 127-33. PubMed PMID: 18089459 4 Maslinska D, Laure-Kamionowska M, Maslinski S. Methyl-CpG binding protein 2, receptors of innate immunity and receptor for advanced glycation end-products in human viral meningoencephalitis. Folia neuropathologica, 2014, 52(4), 428-35. PubMed PMID: 25574748 5 Lu W, Li J, Ren M, Zeng Y, Zhu P, Lin L, Lin D, Hao S, Gao Q, Liang J, Yan L, Yang C. Role of the mevalonate pathway in specific CpG site demethylation on AGEs-induced MMP9 expression and activation in keratinocytes. Molecular and cellular endocrinology, August 2015, 15(411), 121-129. PubMed PMID: 25916956 6 Powers HJ, Hill MH, Welfare M, Spiers A, Bal W, Russell J, Duckworth Y, Gibney E, Williams EA, Mathers JC. Responses of biomarkers of folate and riboflavin status to folate and riboflavin supplementation in healthy and colorectal polyp patients (the FAB2 Study). Cancer epidemiology, biomarkers & prevention, October 2007, 16(10), 2128-35. PubMed PMID: 17932361 7 Figueiredo JC, Levine AJ, Grau MV, Midttun O, Ueland PM, Ahnen DJ, Barry EL, Tsang S, Munroe D, Ali I, Haile RW, Sandler RS, Baron JA. Vitamins B2, B6, and B12 and risk of new colorectal adenomas in a randomized trial of aspirin use and folic acid supplementation. Cancer epidemiology, biomarkers & prevention, August 2008, 17(8), 2136-45. PubMed PMID: 18708408 8Nedrebø BG, Hustad S, Schneede J, Ueland PM, Vollset SE, Holm PI, Aanderud S, Lien EA. Homocysteine and its relation to B-vitamins in Graves' disease before and after treatment: effect modification by smoking. Journal of internal medicine, November 2003, 254(5), 504-12. PubMed PMID: 14535973 9Madigan SM, Tracey F, McNulty H, Eaton-Evans J, Coulter J, McCartney H, Strain JJ. Riboflavin and vitamin B-6 intakes and status and biochemical response to riboflavin supplementation in free-living elderly people. American journal of clinical nutrition, August 1998, 68(2), 389-95. PubMed PMID: 9701198 10Premkumar VG, Yuvaraj S, Shanthi P, Sachdanandam P. Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy. British journal of nutrition, December 2008, 100(6), 1179-82. PubMed PMID: 18377693 11Penberthy WT, Kirkland JB. Niacin. In:Erdman JW, MacDonald I, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Ames: International Life Sciences Institute;2012:293-306 12Sun WP, Li D, Lun YZ, et al. Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives. Hypertension