Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Fatty acid synthesis wikipedia , lookup
Nicotinamide adenine dinucleotide wikipedia , lookup
Adenosine triphosphate wikipedia , lookup
Clinical neurochemistry wikipedia , lookup
Biosynthesis wikipedia , lookup
Butyric acid wikipedia , lookup
Citric acid cycle wikipedia , lookup
Amino acid synthesis wikipedia , lookup
Phar 722 Pharmacy Practice III VitaminsPyridoxine (B6) Spring 2006 Pyridoxine Study Guide • The applicable study guide items in the Vitamin Introduction • History • Nomenclature • Structures of the vitamins and conversion to the cofactor forms • Functions of the cofactor forms including the specific types of reactions • Deficiency conditions • Drug-vitamin interactions • Dietary and commercial forms of the vitamin History • First isolated in 1934 as a factor responsible for curing a type of rat dermatitis. – Much recent research has been conducted at Oregon State University. • There is no historical “disease” associated with this vitamin. • The “importance” of this vitamin was discovered when an infant milk formulation was sold without pyridoxine. – The infants developed convulsions and there were deaths. – Initially, there was confusion as to whether there was a contaminant in the milk. Chemistry • There are three forms of the vitamin. – Pyridoxine is found in plants. • Common commercial form. – Pyridoxal found in animals. • Never commercial. – Pyridoxamine found in animals. • Not found in common vitamin preparations. • The forms found in animals came from eating vegetable sources or other animals. Pyridoxine Uptake and Metabolism • All three forms are absorbed from the intestine and transported to the liver where they are phosphorylated. • All three are interchangeable as their respective phosphate esters. • Transport throughout the body seems to be on serum albumin. • Pyridoxal phosphate is considered the cofactor form of the vitamin. COOCH2OH HO H3C N 4-Pyridoxic Acid (metabolite) Plants FADH2 Oxidase Animals FAD CHO CH2OH HO CH2OH CH2NH3+ + HO NAD+ NADH + H HO CH2OH CH2OH Oxidase Oxidase H3C N H3C Pyridoxine (a commercial form) Phosphatase Pyridoxine P Phosphatase ATP HO ADP Kinase ATP Pi CH2NH3+ CHO CH2OP N N Pyridoxamine (a commerical form) Kinase Phosphatase FMN H3C H3C ADP Pi CH2OH HO FMN Pyridoxal ADP Kinase ATP Pi FMNH2 N HO CH2OP FMNH2 CH2OP Oxidase Oxidase H3C N Pyridoxal P (coenzyme/cofactor) FMNH2 FMN H3C N Pyridoxamine P Biochemical Functions • Transamination: – Nearly every amino acid requires pyridoxal phosphate (PLP) for its metabolism. • Decarboxylation of amino acids: – DOPA to dopamine; – Histidine to histamine; – 5-OH-Tryptophan to serotonin • Production of glucose-1-P from glycogen. • Conversion of homocysteine to cysteine and glycogenic end products. • Other reactions where an amine moiety is part of the reaction scheme. H R C CO2- NH3+ -amino acid + O Deamination H R H2O C CO2- R NH+ C R O CO2- -keto acid NH+ H2O + H C HO CH CH2OP NH3+ CH2 HO CH2OP CO2- C HO CH2OP CH2 HO H3C N H3C N H3C N Aldimine Pyridoxal P H3C H+ R' C R H R H C H R' NH+ NH3+ H2O CO2 - O Decarboxylation H CO2- Transamination CO2- O H H 2O R' CH2OP HO O CH2OP H C HO N C CO2- CH2 Amine HO C C NH+ CH H3C N Pyridoxamine P CO2 R CH2OP H3C -amino acid CH2OP N H3C NH3+ N Pyridoxal P Pyridoxine deficiency-1 • Deficiencies are seen with this vitamin. – In infants there is a characteristic type of convulsions which is reversible when pyridoxine supplements are given. – Deficient infants also show a characteristic electrical encephalogram. (This was "discovered" when infants were fed an infant formula lacking pyridoxine.) • Pyridoxine has shown no beneficial results for adults with convulsive disorders. • The neuropathies seen in pyridoxine deficiencies probably relate to its requirement for the biosynthesis of three neurotransmitters – serotonin from tryptophan and norepinephrine and epinephrine from L-DOPA (Dihdroxyphenylalanine). L-DOPA is formed from tyrosine by DOPA decarboxylase, a pyridoxal P containing enzyme. Pyridoxine deficiency-2 • Considering the central role that this vitamin plays in amino acid metabolism, it is a wonder that there aren't more visible signs of this deficiency. • A change in the glucose tolerance curve has been reported in pyridoxine deficient subjects. • Elevated homocysteine may indicate a pyridoxine deficiency, but it also can indicate problems with folic acid and cobalamin status. • There have been reports that pyridoxine supplements might be beneficial for neuropathies, particularly those that are drug-induced, and carpal tunnel syndrome. • Proof of its role in treating depression and carpal tunnel syndrome is equivocal. • Because it is required in the conversion of tryptophan to niacin, pyridoxine may have a niacin-sparing effect. Drug – Vitamin Interactions-1 • Isoniazid (INH) – The widely used antitubercular drug isoniazid, INH, can induce a pyridoxine deficiency. • A peripheral neuritis develops. • This interaction has no relationship to INH's antitubercular activity. – Therefore, pyridoxine supplements do not require altering INH dosing schedules. • Penicillamine – This drug is a copper chelator used in Wilson’s Disease (copper storage disease) and has two amine groups. • There may have been an interaction of some type with the earlier high dosage oral contraceptives. – This was based on a tryptophan load test. H N O O C H NH2 HO CH2OP + N H3C Isoniazid (INH) Isonicotinic Acid Hydrazide N Pyridoxal P H2O H H N O C N CH2OP HO N N H3C Isoniazid Pyridoxal Adduct Drug – Vitamin Interactions-2 • L-DOPA – Parkinsonian patients taking L-DOPA must restrict their use of pyridoxine containing vitamin supplements to formulations containing only the adult RDA. – Excessive amounts of pyridoxine will cause peripheral decarboxylation of LDOPA (from DOPA decarboxylase in the mucosa) producing dopamine. • This reduces the amount of L-DOPA that will cross the blood brain barrier. Hypervitaminosis Pyridoxine • A certain mystique has built up around this vitamin resulting in individuals overdosing themselves. • Most of this “mystique” focuses on the role of pyridoxal P in the conversion of glycogen to glucose-1-P. – Example: Marathon runners take pyridoxine for the final “boost” to finish the race. • Serious neurological problems have been seen in doses of 1 - 6 gm/day for 2 - 40 months. • Megadosing below 2 gm/day seem safe, but all of this information is based mostly on anecdotal reports. • There is an UL for this vitamin, considerably below the 2 gm/day. Dosage Forms • Commercial Form: – Synthetic pyridoxine DRIs-1 • AI – Infants (0 - 12 months) 0.1 - 0.3 mg/day (≈0.014 mg/kg to ≈0.033 mg/kg) • EAR – – – – – – – – – Children (1 - 13 years) Males (14 - 19 years) Females (14 - 19 years) Men (19 - 50 years) Men (51+ years) Women (19 - 50 years) Women (51+ years) Pregnancy Lactation 0.4 - 0.8 mg/day 1.1 mg/day 1.0 mg/day 1.1 mg/day 1.4 mg/day 1.1 mg/day 1.3 mg/day 1.6 mg/day 1.7 mg/day DRIs-2 • RDA – – – – – – – – – Children (1 - 13 years) Males (14 - 19 years) Females (14 - 19 years) Men (19 - 50 years) Men (51+ years) Women (19 - 50 years) Women (51+ years) Pregnancy Lactation 0.5 - 1.0 mg/day 1.3 mg/day 1.2 mg/day 1.3 mg/day 1.7 mg/day 1.3 mg/day 1.5 mg/day 1.9 mg/day 2.0 mg/day • UL – Children (1 - 18 years) – Adults (19 an older) 30 - 80 mg/day 100 mg/day Food Sources • • • • • Wheat germ Milk Legumes Meat Vegetables • Dietary forms will be the various cofactor structures.