IOM DRI Research Synthesis Workshop June 7-8, 2006

Transcription

1 Discussion of Research Recommendations: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Dietary Reference Intake Research Synthesis Workshop DRI Report on B Vitamins and Issues New knowledge Common genetic variations influence DRIs Metabolomics and DRIs Steven Zeisel Thiamin Riboflavin Niacin Pantothenic acid Patrick Stover Folate B12 B6 Biotin Presentation: Dr. Steve Zeisel 1

2 Thiamin Major gaps Requirements of children, pregnant and lactating women and elderly; indicators on which to base Thiamin requirement. Gaps adverse effects of high dose thiamin No substantial progress since 1998 (PubMed and Roger Butterworth). Riboflavin Major Gaps requirements in children, pregnancy and lactation, elderly. Gaps functional test to augment FAD dependent glutathionine reductase, effects of physical activity. Progress since 1998 (PubMed) Public Health Nutr. 4: , 2001 Ireland, mean daily intake of riboflavin was below the EAR in 12.5% and 20.6% of men and women, respectively. Clin Chem 46: , Riboflavin inversely associate with plasma Hcy in humans, proposed via flavin dependent MTHFR as effect confined to subjects with SNP. J.B.C. 275: , Some flavoenzymes contain both FAD and FMN Arch Opthamol. 123:517-26, 2005 Riboflavin Rx prevents cataracts. Niacin Major Gaps Increased niacin needs secondary to oxidant damage, blood niacin method rather than urinary method currently used Gaps requirements of children, pregnancy and lactation, enhanced nutrient databases that separate food content from fortification. Some progress since 1998 (PubMed and Joel Moss (NIH)). Public Health Nutr. 4: , 2001 Ireland, 20.8% of men and 6.3% of women exceeded the UL for pre-formed niacin. Int J Toxicol. 2005;24 Suppl 5:1-31. Expert panel on toxicity J Biol Chem 2003; 278: Molecular identification of high and low affinity receptors for nicotinic acid. J Clin Invest : G-protein coupled receptor HM74A mediates flushing and releases PGE2 JAMA 2000; 284: Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease. The ADMIT study: a randomized trial. Circulation 2004; 110: (ARBITER) A double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression. Presentation: Dr. Steve Zeisel 2

3 Pantothenic acid Major gaps human requirements esp. children, toxicity, bioavailability from foods, food composition databases. Minor progress since 1998 (PubMed). Nahrung. 47:243-7, Assay in drinks and vitamins. J AOAC Int. 89:285-8, Improved method for analyses in foods. Major gaps role in chronic disease, refine estimates of human requirements (and infant-child requirements, pregnancy lactation), bioavailability, toxicity, metabolic effects, need for functional biomarkers, interrelationships with B12, B6, methionine and folate metabolism Gaps effects of chronic high intake, food composition tables Estrogen induces endogenous synthesis 80% men, postmen women require choline 44% premen women require it Presentation: Dr. Steve Zeisel 3

4 BASELINE REPLETION Day 1 10 (10 days) Day (40 days) 550 mg choline per 100% choline 70 kg bwt. daily 550 mg/ 70 kg 75% 50% DEPLETION Day (42 days) < 50 mg choline per 70 kg bwt. daily 25% The baseline diet also contains 400 mg folate, while the Depletion and Repletion diets have 100 µg folate. On Day 11, subjects are randomized to 100 µg folate (placebo) or 400 µg (folic acid) for the remainder of the study. Liver damage Mean CPK AST Level (U/L) (U/L) * Normal Diet Depletion Repletion Phase Of Study Muscle damage Mean CPK Level (U/L) Normal Diet Depletion Repletion Phase Of Study Presentation: Dr. Steve Zeisel 4

5 Diet plus endogenous synthesis Phosphatidylethanolamine N- methyltransferase (PEMT) phosphatidylcholine PtdEthanolamine S-adenosylmethionine Estrogen induces PEMT gene Estrogen induces endogenous synthesis 80% men, postmen women require choline 44% premen women require it SNP in PEMT promoter makes women susceptible to choline deficiency Women with PEMT -774G>C OR=25 18% were CC, 56% GC, and 26% GG (FASEB J, in press) Formyl-THF MTHFD1 Methylene- THF Methyl-THF Met Hcy Presentation: Dr. Steve Zeisel 5

6 Estrogen induces endogenous synthesis 80% men, postmen women require choline 44% premen women require it SNP in PEMT promoter makes women susceptible to choline deficiency Women with PEMT -774G>C OR=25 18% were CC, 56% GC, and 26% GG (FASEB J, in press) Premen Women with MTHFD1 1958G>A OR=85 11% were AA, 52% GA, and 37% GG (PNAS 102: , 2006) Some men require more than current AI some men needed 825 mg/70kg/d (AI 550) New functional markers (add to liver damage) muscle damage (AJCN 80: , 2004) lymphocyte apoptosis (AJCN in press) elevated Hcy after Met load (AJCN 81: , 2004) New epidemiology data in humans women eating low choline have 4x risk of baby with NTD (Am J Epid 160: , 2004) and 1.75x risk of cleft lip-palate (Epidemiology 17: , 2006) -betaine inversely relate to plasma homocysteine in humans Am J Clin Nutr Jul;82(1): choline Rx Am J Clin Nutr Jun;81(6): Betaine Rx Am J Clin Nutr Apr;83(4): Framingham offspring 350 Food composition data now available mg/100 g food Beef Liver Egg Wheat germ Bacon Soy Bean (dried) Cod Ground beef Chicken Peanut Butter Milk chocolate Tofu Bread Spinach Cow Milk Presentation: Dr. Steve Zeisel 6

7 Summary of progress Major gaps role in chronic disease, refine estimates of human requirements (and infant-child requirements, pregnancy lactation), bioavailability, toxicity, metabolic effects, need for functional biomarkers, interrelationships with B12, B6, methionine and folate metabolism Gaps effects of chronic high intake, food composition tables Presentation: Dr. Steve Zeisel 7