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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/15 02:48:45」(JST)

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Pyridoxamine is a vitamer in the vitamin B₆ family, which includes pyridoxal and pyridoxine. Pyridoxamine is converted to the biologically active form of vitamin B₆, pyridoxal 5-phosphate, via the vitamin B₆ salvage pathway.^[1] Vitamin B₆ acts as an enzyme cofactor in a variety of metabolic processes. In food, pyridoxamine is commonly found as a 5’-phosphate derivative, which is hydrolyzed by intestinal phosphatases to pyridoxamine and absorbed in the jejunum.^[2] Absorbed pyridoxamine is converted to pyridoxamine 5’-phosphate by pyridoxal kinase, which is further converted to the active pyridoxal 5-phosphate by pyridoxamine-phosphate transaminase or pyridoxine 5’-phosphate oxidase.^[3]

Pyridoxamine is based on a pyridine ring structure, with hydroxyl, methyl, aminomethyl, and hydroxymethyl substituents. It differs from pyridoxine by the substituent at the 4-position. The phenol at position 3 and aminomethyl group at position 4 of its ring endow pyridoxamine with a variety of chemical properties, including the scavenging of free radical species and carbonyl species formed in sugar and lipid degradation and chelation of metal ions that catalyze Amadori reactions.^[4]

Research

Pyridoxamine can form fairly weak complexes with a number of transition metal ions, with a preference for Cu²⁺ and Fe³⁺.^[5] The 3'-hydroxyl group of pyridoxamine allows for efficient hydroxyl radical scavenging.^[5]

Pyridoxamine inhibits the Maillard reaction and can block the formation of advanced glycation endproducts,^[6] which are associated with medical complications of diabetes.^[7] Pyridoxamine is hypothesized to trap intermediates in the formation of Amadori products released from glycated proteins, possibly preventing the breakdown of glycated proteins by disrupting the catalysis of this process through disruptive interactions with the metal ions crucial to the redox reaction.^[8] One research study found that pyridoxamine specifically reacts with the carbonyl group in Amadori products, but inhibition of post-Amadori reactions (that can lead to advanced glycation endproducts) is due in much greater part to the metal chelation effects of pyridoxamine.^[4]

A variety of preclinical studies in animal models of diabetes indicated that pyridoxamine improved kidney histology comparable or superior to aminoguanidine.^[8] Because of these results, pyridoxamine has been investigated for clinical utility in the treatment of diabetic nephropathy.^[8]^[9]

Pyridoxamine also inhibits the formation of advanced lipoxidation endproducts during lipid peroxidation reactions by reaction with dicarbonyl intermediates.^[10] In other preclinical research, pyridoxamine may be efficacious in treating diabetic neuropathy and retinopathy associated with diabetes^[8]^[10] and kidney stone disease.^[5] In one study, pyridoxamine was more effective at protecting from ionizing radiation-induced gastrointestinal epithelial apoptosis than amifostine (the only radioprotector currently Food and Drug Administration (FDA)-approved) due to pyridoxamine reactive oxygen species and reactive carbonyl species scavenging profile.^[11]

FDA Regulatory Activity

Pyridoxamine was marketed as a dietary supplement, often as the hydrochloride salt, pyridoxamine dihydrochloride. However, in the United States, the FDA ruled in January 2009 that pyridoxamine must be regulated as a pharmaceutical drug because it is the active ingredient in Pyridorin, a drug designed by Biostratum, Inc., to prevent the progression of diabetic nephropathy.^[12]^[13]^[14]^[15]

Pyridorin had success in early clinical trials, found to be effective in slowing the progression of diabetic neuropathy in a phase II trial on 224 patients.^[13] However, in 2005 Biostratum ran out of money and so was unable to begin a Phase III trial.^[13] Investors in Biostratum had realized that because Biostratum had no patent on pyridoxamine itself, and that pyridoxamine was commonly available for purchase as a dietary supplement, the company would be unable to charge enough money for the treatment (should it be approved as a prescription drug by the FDA) for the investors to get a reasonable return on the investment they had already made (about $100M) much less on the additional investment a Phase III trial would require.^[13] To solve this problem, Biostratum submitted a Citizen Petition to the FDA on July 29, 2005, seeking to disallow sales of pyridoxamine-containing supplements on the grounds that pyridoxamine, as the subject of an Investigational New Drug Application with the FDA, is a drug and not a dietary supplement.^[13] This petition was opposed by the Council for Responsible Nutrition, a trade association of the dietary supplement industry.^[13] On January 12, 2009, the FDA ruled that products containing pyridoxamine are excluded from the definition of dietary supplements as defined by the Dietary Supplement Health and Education Act of 1994.^[14] The FDA stated that the status of Pyridorin as an investigational new drug, as a result of an application filed by BioStratum in July 1999 and effective on September 1, 1999, meant that "the marketing of pyridoxamine in a dietary supplement is essentially equivalent to the marketing of an investigational new drug as a dietary supplement" because there was an "absence of independent, verifiable evidence that the substance was marketed as a food or a dietary supplement prior to its authorization for investigation as a new drug."^[16]

In 2006, Biostratum licensed its rights in Pyridorin to another company, NephroGenex ^[17] In 2008, NephroGenex restarted the clinical development of Pyridorin, which as of 2012 is still ongoing.^[18]

Patenting Activity

A patent application claiming pharmaceutical compositions of pyridoxamine, and methods to use pyridoxamine to treat diabetic complications, was filed by Biostratum and was published in 2004.^[19] The application does not claim pyridoxamine itself.

References

^ Roje S (2007). "Vitamin B biosynthesis in plants". Phytochemistry 68 (14): 1904–21. doi:10.1016/j.phytochem.2007.03.038. PMID 17512961.
^ Merrill AH, Henderson JM (1990). "Vitamin B6 metabolism by human liver". Ann. N. Y. Acad. Sci. 585 (1 Vitamin B6): 110–7. doi:10.1111/j.1749-6632.1990.tb28047.x. PMID 2192606.
^ Ink SL, Henderson LM (1984). "Vitamin B6 metabolism". Annu. Rev. Nutr. 4 (1): 455–70. doi:10.1146/annurev.nu.04.070184.002323. PMID 6380540.
^ ^a ^b Adrover M, Vilanova B, Frau J, Muñoz F, Donoso J (May 2008). "The pyridoxamine action on Amadori compounds: A reexamination of its scavenging capacity and chelating effect". Bioorg. Med. Chem. 16 (10): 5557–69. doi:10.1016/j.bmc.2008.04.002. PMID 18434162.
^ ^a ^b ^c Voziyan PA, Hudson BG (2005). "Pyridoxamine as a multifunctional pharmaceutical: targeting pathogenic glycation and oxidative damage". Cell. Mol. Life Sci. 62 (15): 1671–81. doi:10.1007/s00018-005-5082-7. PMID 15905958.
^ Voziyan PA, Hudson BG (2005). "Pyridoxamine: the many virtues of a maillard reaction inhibitor". Ann. N. Y. Acad. Sci. 1043 (1): 807–16. doi:10.1196/annals.1333.093. PMID 16037308.
^ Ahmed N, Thornalley PJ (2007). "Advanced glycation endproducts: what is their relevance to diabetic complications?". Diabetes Obes Metab 9 (3): 233–45. doi:10.1111/j.1463-1326.2006.00595.x. PMID 17391149.
^ ^a ^b ^c ^d Giannoukakis N (2005). "Pyridoxamine (BioStratum)". Curr Opin Investig Drugs 6 (4): 410–8. PMID 15898348.
^ Williams ME, Bolton WK, Khalifah RG, Degenhardt TP, Schotzinger RJ, McGill JB (2007). "Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy". Am. J. Nephrol. 27 (6): 605–14. doi:10.1159/000108104. PMID 17823506.
^ ^a ^b Metz TO, Alderson NL, Thorpe SR, Baynes JW (2003). "Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications". Arch. Biochem. Biophys. 419 (1): 41–9. doi:10.1016/j.abb.2003.08.021. PMID 14568007.
^ Thotala D, Chetyrkin S, Hudson B, Hallahan D, Voziyan P, Yazlovitskaya E (September 2009). "Pyridoxamine protects intestinal epithelium from ionizing radiation-induced apoptosis". Free Radic. Biol. Med. 47 (6): 779–85. doi:10.1016/j.freeradbiomed.2009.06.020. PMC 2739572. PMID 19540915.
^ "FDA finds vitamin B6 form not legal in supplements", newsfood.com, February 2, 2009
^ ^a ^b ^c ^d ^e ^f "Big problem for BioStratum", Triangle Business Journal, October 14, 2005
^ ^a ^b "FDA's pyridoxamine decision: FDA's decision regarding pyridoxamine has larger implications for dietary ingredients in general", Entrepreneur, April, 2009
^ http://www.regulations.gov/#!documentDetail;D=FDA-2005-P-0259-0004
^ FDA-2005-P-0259-0004: FDA Response to Biostratum, Inc. (Kathleen M Sanzo, Esq) - Petition Partial Approved and Denial
^ http://www.renalbusiness.com/news/2006/05/nephrogenex-acquires-rights-to-diabetic-nephropat.aspx
^ http://www.nephrogenex.com/NGX_News.htm
^ (WO/2004/112788) PYRIDOXAMINE FOR THE TREATMENT OF DIABETIC KIDNEY DISEASE, World Intellectual Property Organization

External links

Clinical trials testing Pyridoxamine (clinicaltrials.gov):
- Effect of Pyridorin in Patients With Diabetic Nephropathy (NCT00320060)
- Effect of Pyridorin in Patients With Diabetic Nephropathy (NCT00320021)
- Safety and Efficacy Study of Pyridorin in Patients With Nephropathy Due to Type 2 Diabetes (NCT00734253)

UpToDate Contents

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1. 水溶性ビタミンの概要 overview of water soluble vitamins
2. 糖尿病性腎症の治療 treatment of diabetic nephropathy
3. 新生児痙攣の治療 treatment of neonatal seizures
4. 点頭てんかんの病因および発症機序 etiology and pathogenesis of infantile spasms
5. 新生児痙攣の病因および予後 etiology and prognosis of neonatal seizures

English Journal

Endogenous formation of N(ε)-(Carboxymethyl)lysine is increased in fatty livers and induces inflammatory markers in an in vitro model of hepatic steatosis.

Gaens KH, Niessen PM, Rensen SS, Buurman WA, Greve JW, Driessen A, Wolfs MG, Hofker MH, Bloemen JG, Dejong CH, Stehouwer CD, Schalkwijk CG.SourceDepartment of Internal Medicine, Laboratory of Metabolism and Vascular Medicine; Cardiovascular Research Institute Maastricht University Medical Center, Maastricht, The Netherlands.
Journal of hepatology.J Hepatol.2011 Sep 8. [Epub ahead of print]
BACKGROUND: Increased lipid peroxidation and inflammation are major factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A lipoxidation product that could play a role in the induction of hepatic inflammation is N(ε)-(Carboxymethyl)lysine (CML). The aim of the present study was t
PMID 21907687

Oxidative stress and the etiology of insulin resistance and type 2 diabetes.

Henriksen EJ, Diamond-Stanic MK, Marchionne EM.AbstractThe condition of oxidative stress arises when oxidant production exceeds antioxidant activity in cells and plasma. The overabundance of oxidants is mechanistically connected to the multifactorial etiology of insulin resistance, primarily in skeletal muscle tissue, and the subsequent development of type 2 diabetes. Two important mechanisms for this oxidant excess are (1) the mitochondrial overproduction of hydrogen peroxide and superoxide ion under conditions of energy surplus and (2) the enhanced activation of cellular NADPH oxidase via angiotensin II receptors. Several recent studies are reviewed that support the concept that direct exposure of mammalian skeletal muscle to an oxidant stress (including hydrogen peroxide) results in stimulation of the serine kinase p38 mitogen-activated protein kinase (p38 MAPK), and that the engagement of this stress-activated p38 MAPK signaling is mechanistically associated with diminished insulin-dependent stimulation of insulin signaling elements and glucose transport activity. The beneficial interactions between the antioxidant α-lipoic acid and the advanced glycation end-product inhibitor pyridoxamine that ameliorate oxidant stress-associated defects in whole-body and skeletal-muscle insulin action in the obese Zucker rat, a model of prediabetes, are also addressed. Overall, this review highlights the importance of oxidative stress in the development of insulin resistance in mammalian skeletal muscle tissue, at least in part via a p38-MAPK-dependent mechanism, and indicates that interventions that reduce this oxidative stress and oxidative damage can improve insulin action in insulin-resistant animal models. Strategies to prevent and ameliorate oxidative stress remain important in the overall treatment of insulin resistance and type 2 diabetes.
Free radical biology & medicine.Free Radic Biol Med.2011 Sep 1;51(5):993-9. Epub 2010 Dec 13.
The condition of oxidative stress arises when oxidant production exceeds antioxidant activity in cells and plasma. The overabundance of oxidants is mechanistically connected to the multifactorial etiology of insulin resistance, primarily in skeletal muscle tissue, and the subsequent development of t
PMID 21163347

Japanese Journal

α-ケトエステルのバイオミメティックトランスアミノ化反応

阿部匠
有機合成化学協会誌 71(1), 62-63, 2013
… Vitamine B6-dependent aminotransferase-catalyzed transamination of α-keto acids from pyridoxamine is an important process to generate α-amino acids in nature. …
NAID 130003373261

Contents of All Forms of Vitamin B6, Pyridoxine-β-Glucoside and 4-Pyridoxic Acid in Mature Milk of Japanese Women According to 4-Pyridoxolactone-Conversion High Performance Liquid Chromatography

YAGI Toshiharu,IWAMOTO Saya,MIZUSEKI Rie,FURUYA Michi,NAKAYAMA Kazuko
Journal of Nutritional Science and Vitaminology 59(1), 9-15, 2013
… Pyridoxamine, pyridoxine, pyridoxamine 5'-phosphate, pyridoxine 5'-phosphate, and pyridoxine-β-glucoside were found in 15, 14, 13, 9, and 7 samples, respectively. …
NAID 130003368153

Generation of superoxide anions by a glycation reaction in conventional laboratory media(MICROBIAL PHYSIOLOGY AND BIOTECHNOLOGY)

Nakashima Takuji,Omura Satoshi,Takahashi Yoko
Journal of bioscience and bioengineering 114(3), 275-280, 2012-09
… In addition, the O^-_2 generation from BHI medium was significantly inhibited by pyridoxamine that is a Maillard reaction inhibitor. …
NAID 110009517377

Related Pictures

★リンクテーブル★

リンク元	「ビタミンB6」
拡張検索	「pyridoxamine phosphate oxidase」「pyridoxamine phosphate」

「ビタミンB6」

Pyridoxamine
	IUPAC name 4-(aminomethyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol
Identifiers
CAS number	85-87-0
PubChem	1052
ChemSpider	1023
KEGG	C00534
ChEBI	CHEBI:16410
ChEMBL	CHEMBL593019
Jmol-3D images	Image 1
	SMILES Oc1c(c(cnc1C)CO)CN ;
	InChI InChI=1S/C8H12N2O2/c1-5-8(12)7(2-9)6(4-11)3-10-5/h3,11-12H,2,4,9H2,1H3 ; Key: NHZMQXZHNVQTQA-UHFFFAOYSA-N InChI=1/C8H12N2O2/c1-5-8(12)7(2-9)6(4-11)3-10-5/h3,11-12H,2,4,9H2,1H3; Key: NHZMQXZHNVQTQA-UHFFFAOYAS ;
Properties
Molecular formula	C8H12N2O2
Molar mass	168.19 g mol−1
	Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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	Infobox references