A naturally occurring B6 vitamer with strong glycation inhibiting properties

Below we present a summary of the major research results for this chemical, taken from published studies in the scientific peer-reviewed literature. For the latest information on the progress of this vitamer towards establishment acceptance as a therapeutic modality for recognized diseases, see BioStratum Inc. - Pyridorin

Relationship to Vitamin B6

Pyridoxamine (PM) is one of 3 naturally occurring vitamers of Vitamin B6. The other B6 vitamers are pyridoxal (PL) and pyridoxine (PN), the latter being the form primarily used in supplements currently produced by suppliers. PN is found mainly in plant sources and PM and PL are found almost exclusively in animal sources. In addition there are many variants of these 3 basic forms which have added moieties. Particularly common are the phosphorylated forms which are found mainly in animal tissues. The phosphorylated forms of many vitamins are particularly important because they are usually also the active or "coenzyme" form required by enzymatic reactions which make catalytic use of the vitamin. These forms are named by adding the word "phosphate" and are abbreviated by adding "P" to the end of the abbreviation (ie. PMP, PLP *, PNP). However PNP is not a coenzyme and therefore, both PN and PNP are biochemically of no value to the human body until they are first converted to PLP. The conversions of PN to PL and PNP to PLP are not reversible and no direct conversion of PN to PM nor PNP to PMP occurs. The conversions of PM to PL and PMP to PLP are reversible and an equilibrium concentration of approximately 1:5 of PMP:PLP is normal present in human serum.R
While the B6 vitamin activity of all its vitamers is comparable since the body contains interconversion enzymes, the activity of PM as an amino acid or protein glycation inhibitor has been shown to be superior to that of PN, PL and PLP.R

* Note: Many supplement suppliers refer to pyridoxal phosphate by the abbreviation P5P because the phosphate group is attached to the hydroxymethyl group that is attached to the number 5 position on the pyridine ring; however PLP is the abbreviation used in the nutritional and biomedical literature.

Safety and Interactions

  1. Various forms of vitamin B6 have been used for decades for dietary supplemental and medical therapeutic purposes. Although PM has not itself been used as much as other forms, all indications are that its safety and toxicity profile should be at least as good as the other forms.
  2. In chronic use at a dose under 100 mg daily, there are no reports of any negative effects from the use of vitamin B6.
  3. Doses of vitamin B6 > 10 mg/day may reduce the efficacy of certain drugs.R
  4. Doses of vitamin B6 in the range 500-1000 mg/day have resulted in a small number of instances of neurotoxicity,R and photosensitivity.R However, in all of these instances the vitamer given was PN which is converted to PL and PLP in the liver without involvement elsewhere. Since PM is not active until converted to PMP or PLP (via PMP),R its diversion to glycation and AGE inhibitions may mean that dosages of PM which create B6 toxicity are greater than of PN. Unfortunately, this has not been experimentally proven or disproven.
  5. Aminoguanidine attaches to the carbonyl groups of PL and PLP and inhibits their activity.R1,R2 However, since PM does not contain a carbonyl group, aminoguanidine will not inhibit its activity. Since PM can easily be converted to PMP and PLP, administration of PM may reasonably be considered as an antidote to potential aminoguanidine toxicity. Unfortunately, this has not been experimentally verified.
  6. "Large doses of pyridoxine cause injury to the primary sensory neurons in trigeminal and dorsal root ganglia of animals and patients subjected to megavitamin therapy. ... the neurotoxicity of pyridoxine for rats was found to be increased by dietary protein deficiency. ... The vitamers related to pyridoxine (pyridoxal, pyridoxamine) and the coenzyme (pyridoxal 5-phosphate) did not cause clinical signs or lesions similar to those produced by pyridoxine even when injected in maximum tolerated doses. Neither a protein-deficient diet nor bilateral nephrectomy changed the results with the vitamers."R

Proven Benefits

  1. A "lipid glycation inhibitor has not been discovered yet due to lack of a lipid glycation model study useful for inhibitor screening. Consequently, we optimized and developed a lipid glycation model considering various reaction conditions (glucose concentration, temperature, buffer type and pH) between phosphatidylethanolamine (PE) and glucose. Using the developed model, various protein glycation inhibitors (aminoguanidine, pyridoxamine, aspirin and carnosine), antioxidants (ascorbic acid, alpha-tocopherol, quercetin and rutin) and other food compounds (L-lysine, L-cysteine, pyridoxine, pyridoxal and pyridoxal 5'-phosphate) were evaluated for their anti-glycative property. As results, pyridoxal 5'-phosphate and pyridoxal (vitamin B(6) derivatives) were the most effective anti-glycative compounds. These pyridoxals could easily be condensed with PE before glucose/PE reaction occurred. Since we found that PE-pyridoxal 5'-phosphate adduct was detectable in human red blood cells and that elevated plasma Amadori-PE concentration in streptozotocin-induced diabetic rats was decreased by dietary supplementation of pyridoxal 5'-phosphate, it is likely that pyridoxal 5'-phosphate acts as lipid glycation inhibitor in vivo, which possibly contributes to diabetes prevention." [Note that this result is for lipid glycation, which is much rarer and less harmful than protein glycation. In addition, pyridoxamine is completely interconvertible to and from pyridoxal and pyridoxal 5'-phosphate.]R
  2. "These results, coupled with favorable toxicity profiles of PM in humans, show promise for the therapeutic use of PM in primary hyperoxaluria and other kidney stone diseases."R
  3. "Pyridoxamine, a promising drug for treatment of diabetic nephropathy, protected cell adhesion and integrin binding from inhibition by MGO [the ubiquitous carbonyl compound methylglyoxal]."R
  4. [In a rat model of some of the negative effects of diabetes,] "an infusion of Ang II [angiotensin II] increased the serum and renal accumulation of AGE and advanced oxidation protein products and induced renal hypertrophy and salt retention that could be antagonized [these negative effects could be reduced] by pyridoxamine."R
  5. [When incubated together in vitro,] "PM also greatly inhibited the lipofuscin-like fluorescence formation induced by MDA [malondialdehyde] reaction with bovine serum albumin" and this led researchers to conclude: "Our results showed clearly that PM inhibited the formation of ALEs [advanced lipoxidation end products] by trapping MDA directly under physiological condition, and provide insight into the mechanism of action of PM in protecting proteins against carbonyl stress."R
  6. "The antioxidant effects of natural vitamin B(6) compounds on Schizosaccharomyces pombe [yeast] cells treated with menadione sodium bisulfite (water soluble menadione and a generator of superoxide, MSB) and the mechanism underlying the function were examined with the yeast cells treated with pyridoxal 5' phosphate. Vitamin B(6) compounds showed no ex vivo reactivity toward MBS at pH 5.5 or 7.0. The yeast cells showed no growth in the medium containing 1.0 mM MSB. The coexistence of 1.0 mM of each vitamin B(6) compound supported the growth of the yeast cells. The efficacy order was pyridoxal 5'-phosphate>/=pyridoxamine 5'-phosphate>pyridoxamine>pyridoxal>/=pyridoxine. The first three compounds showed higher antioxidant activity than vitamin C did."R
  7. "Pretreatment of the cultures [renal proximal tubule cells (PTCs)] with either 1) aminoguanidine or pyridoxamine (inhibitors of the accumulation of advanced glycation end products), 2) rotenone (an inhibitor of the mitochondrial electron transport chain), or 3) apocynin or diphenylene iodonium (DPI; inhibitors of NADPH oxidase) blocked the observed changes that occurred as a consequence of the incubation of the PTCs with high glucose. Included among these changes were the observed increase in H2O2 levels, as well as an increase in lipid peroxide production, and a decrease both in the activity of catalase and in the level of glutathione (GSH), endogenous antioxidants. ... Other related changes observed in the PTCs that could be reversed by treatment with either aminoguanidine, pyridoxamine, rotenone, apocynin, or DPI included an increase in transforming growth factor-beta1 secretion and the activation of the NF-kappaB signal transduction pathway."R
  8. "[Streptozotocin induced diabetic rats] were both hyperglycaemic and dyslipidaemic, and showed evidence of early nephropathy (albuminuria, creatinaemia). All interventions limited the progression of nephropathy, without affecting glycaemia. The order of efficacy was: pyridoxamine (650 > vitamin E (200 > lipoic acid (93 approximately enalapril (35 Pyridoxamine also significantly inhibited AGE/ALE accumulation in tissues; effects of other agents were mixed, but the degree of renoprotection was consistent with their effects on AGE/ALE formation."R
  9. "These data suggest that NAC [N-acetyl-L-cysteine] and PM treatment of SZ-injected [streptozotocin induced] diabetic hamsters reduces oxidative stress and restores beta-cell function,"R
  10. "1,4-Dicarbonyl compounds, ... exhibit severe toxicity. The key step in the toxicity of these compounds is their reaction with the lysyl residues of proteins to form pyrrole adducts. ... We found pyridoxamine (PM) to react extremely rapidly, with a second-order rate constant at physiological pH being approximately 2300 times faster than that of Nalpha-acetyllysine. The extreme reactivity of PM was unique to 1,4-dicarbonyls, as its reactions with methylglyoxal and 4-hydroxy-2(E)-nonenal were much slower and only slightly faster than with Nalpha-acetyllysine."R
  11. "Newer anti-AGE agents include pyridoxamine and the so-called 'amadorins', cross-link breakers, AGE binders and receptor antagonists."R
  12. "We conclude that the PM functions, at least in part, by trapping intermediates in AGE/ALE formation and propose a mechanism for PM inhibition of AGE/ALE formation involving cleavage of alpha-dicarbonyl intermediates in glycoxidation and lipoxidation reactions."R
  13. "Lipids are an important source of chemical modification of tissue proteins, even in the absence of hyperglycemia. PM inhibited AGE/ALE formation and hyperlipidemia and protected against renal and vascular pathology in a nondiabetic model."R
  14. "These results indicate that the AGE/ALE inhibitor PM protected against a range of pathological changes in the diabetic retina and may be useful for treating diabetic retinopathy."R
  15. "Our studies show that pyridoxamine reduces oxidative stress and AGE formation. We suspect that a direct interaction of pyridoxamine with MG [the alpha-dicarbonyl compound methylglyoxal] partly accounts for AGE inhibition."R
  16. This paper clearly shows that PM is better than AG for rats with induced diabetes. Unfortunately, the attempt to show some benefits in controls treated with only PM was not successful, partly because insufficient PM was given to them in their drinking water. However, even so there was a 10% weight reduction caused by administration of PM. Here are some quotes from the abstract and full paper.
    In streptozotocin-diabetic rats treated with pyridoxamine and in parallel with aminoguanidine, the prototype AGE inhibitor, "pyridoxamine significantly inhibited the increase in albuminuria, plasma creatinine, hyperlipidemia and plasma lactate/pyruvate ratio without an effect on blood glucose or glycated hemoglobin. AGE/ALEs, fluorescence and cross-linking of skin collagen increased approximately twofold in diabetic versus control rats after seven months of diabetes. Pyridoxamine caused a significant (25 to 50%) decrease in the advanced glycation and lipoxidation end products (AGE/ALEs), carboxymethyllysine and carboxyethyllysine, in cross-linking and fluorescence in skin collagen of diabetic rats, but did not affect pentosidine. Pyridoxamine and aminoguanidine had similar effects on parameters measured, supporting a mechanism of action involving AGE/ALE inhibition.
    "Although both AG and PM inhibited the chemical modification of protein by ribose and glucose in vitro, on PM was effective in inhibiting the formation of AGEs from Amadori adducts on glycated proteins, prepared by anaerobic incubation with ribose or glucose. Thus, there is an overlap in the AGE-inhibitory activity of these compounds, with PM having a broader range of inhibitory activity, that is, inhibition of post-Amadori reactions."R
  17. "PM also inhibited the modification of lysine residues and loss of enzymatic activity of RNase in the presence of GO (glyoxal) and GLA (glycolaldehyde) and inhibited formation of the AGE/ALE N(epsilon)-(carboxymethyl)lysine during reaction of GO and GLA with bovine serum albumin. Our data suggest that the AGE/ALE (advanced glycation/lipoxidation end products) inhibitory activity and the therapeutic effects of PM observed in diabetic animal models depend, at least in part, on its ability to trap reactive carbonyl intermediates in AGE/ALE formation, thereby inhibiting the chemical modification of tissue proteins."R
  18. "Intracellular AGEs (most likely derived from methylglyoxal) crosslink cytoskeletal proteins and render them insoluble. These aggregates inhibit cellular functions including transport processes and contribute to neuronal dysfunction and death. ... Drugs, which inhibit the formation of AGEs by specific chemical mechanisms (AGE-inhibitors), including aminoguanidine, carnosine, tenilsetam, OPB-9195 and pyridoxamine, attenuate the development of (AGE-mediated) diabetic complications."R
  19. "At therapeutic concentrations, the chelating activity of AGE inhibitors and AGE breakers may contribute to their inhibition of AGE formation and protection against development of diabetic complications."R
  20. "Both P (pyridoxine) and PM (pyridoxamine) significantly lowered lipid peroxidation and glycated hemoglobin (HbA1c) formation in high glucose-exposed RBC. P and PM significantly prevented the reduction in (Na+ + K+)-ATPase activity in high glucose-treated RBC. Thus, P or PM can inhibit oxygen radical production, which in turn prevents the lipid peroxidation, protein glycosylation, and (Na+ + K+)-ATPase activity reduction induced by the hyperglycemia."R
  21. "Maillard or browning reactions lead to formation of advanced glycation end products (AGEs) on protein and contribute to the increase in chemical modification of proteins during aging and in diabetes. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) have proven effective in animal model and clinical studies as inhibitors of AGE formation and development of diabetic complications.
    "We report here that PM also inhibits the chemical modification of proteins during lipid peroxidation (lipoxidation) reactions in vitro, and we show that it traps reactive intermediates formed during lipid peroxidation. In reactions of arachidonate with the model protein RNase, PM prevented modification of lysine residues and formation of the advanced lipoxidation end products (ALEs): N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, malondialdehyde-lysine, and 4-hydroxynonenal-lysine. PM also inhibited lysine modification and formation of ALEs during copper-catalyzed oxidation of low density lipoprotein...
    PM, as a potent inhibitor of both AGE and ALE formation, may prove useful for limiting the increased chemical modification of tissue proteins and associated pathology in aging and chronic diseases, including both diabetes and atherosclerosis."R
  22. "Atherosclerosis may be viewed as an age-related disease initiated by nonenzymatic, chemical reactions in a biological system. The peroxidation of lipids in lipoproteins in the vascular wall leads to local production of reactive carbonyl species that mediate recruitment of macrophages, cellular activation and proliferation, and chemical modification of vascular proteins by advanced lipoxidation end-products (ALEs). The ALEs and their precursors affect the structure and function of the vascular wall, setting the stage for atherogenesis. The increased risk for atherosclerosis in diabetes may result from additional carbonyl production from carbohydrates and additional chemical modification of proteins by advanced glycation end-products (AGEs). Failure to maintain homeostasis and the increase in oxidizable substrate (lipid) alone, rather than oxidative stress, is the likely source of the increase in reactive carbonyl precursors and the resultant ALEs and AGEs in atherosclerosis. Nucleophilic AGE-inhibitors, such as aminoguanidine and pyridoxamine, which trap reactive carbonyls and inhibit the formation of AGEs in diabetes, also trap bioactive lipids and precursors of ALEs in atherosclerosis. These drugs should be effective in retarding the development of atherosclerosis, even in nondiabetic patients."R
  23. "The present review focuses on the background and progress that led to discovery of specific inhibition of post-Amadori formation of advanced glycation end products, or AGEs. The "classic" or Hodge pathway begins with glucose condensation with amino groups to form a Schiff base aldimine adduct that undergoes rearrangement to a ketoamine Amadori product. This pathway is considered an important route to AGE formation that has been implicated in glucose-mediated damage in vivo. ... "Amadorins," which we define here as inhibitors of the conversion of Amadori intermediates to AGEs in the absence of excess free or reversibly bound (Schiff base) sugar. Our screening assay then led to the identification of pyridoxamine (Pyridorin) as the first member of this class of Amadorin compounds. ... In view of the importance of Amadori compounds as intermediates in AGE formation in vivo, the therapeutic potential of Pyridorin is currently being investigated and is now showing highly promising results in different animal models."R
  24. "Of several derivatives of vitamins B1 and B6 recently studied for possible AGE inhibition in the presence of glucoseR, pyridoxamine and, to a lesser extent, thiamine pyrophosphate proved to be novel and effective post-Amadori inhibitors that decrease the final levels of AGEs formed."R
  25. "Nonenzymatic glycation of proteins by glucose leading to the formation of toxic and immunogenic advanced glycation end products (AGEs) may be a major contributor to the pathological manifestations of diabetes mellitus, aging, and, possibly, neurodegenerative diseases such as Alzheimer's. We tested the in vitro inhibition of antigenic AGE formation on bovine serum albumin, ribonuclease A, and human hemoglobin by various vitamin B1 and B6 derivatives. Among the inhibitors, pyridoxamine and thiamine pyrophosphate potently inhibited AGE formation and were more effective than aminoguanidine, suggesting that these two compounds may have novel therapeutic potential in preventing vascular complications of diabetes. An unexpected finding was that aminoguanidine inhibited the late kinetic stages of glycation much more weakly than the early phase."R

Potential Benefits

  1. [In rats, with ethylene glycol induced hyperoxaluria,] "These results, coupled with favorable toxicity profiles of PM in humans, show promise for the therapeutic use of PM in primary hyperoxaluria and other kidney stone diseases."R
  2. "Pyridoxamine given in uremic rats with peritoneal dialysis significantly improved functional and structural alterations. ... Pyridoxamine may be beneficial in protection of uremic peritoneal membrane on peritoneal dialysis."R
  3. [In rats, with ethylene glycol induced hyperoxaluria,] "Pyridoxamine treatment resulted in significantly lower (by approximately 50%) levels of urinary glycolate and oxalate excretion compared to untreated hyperoxaluric animals. This was accompanied by a significant reduction in calcium oxalate crystal formation in papillary and medullary areas of the kidney. CONCLUSION: These results, coupled with favorable toxicity profiles of pyridoxamine in humans, show promise for therapeutic use of pyridoxamine in primary hyperoxaluria and other kidney stone diseases."R
  4. "Because the mechanism of interference with redox metal catalysis is operative under the conditions closely mimicking the diabetic state, it may contribute significantly to PM efficacy in preventing diabetic complications in vivo."R.
  5. "Assuming that 'carbonyl stress' contributes significantly to the progression of Alzheimer's disease, AGE-inhibitors [including aminoguanidine, carnosine, tenilsetam, OPB-9195 and pyridoxamine] might also become interesting novel therapeutic drugs for treatment of AD."R

Reviews and Additional Reading

  1. "Investigation of the PM mechanism of action demonstrated that PM inhibits post-Amadori steps of the Maillard reaction by sequestering catalytic metal ions and blocking oxidative degradation of Amadori intermediate. PM also has the capacity to scavenge toxic carbonyl products of sugar and lipid degradation, and to inhibit reactive oxygen species. These multiple activities position PM as a promising drug candidate for treatment of multifactorial chronic conditions in which oxidative reactions and/or carbonyl compounds confer pathogenicity."R
  2. "Several approaches have been used to inhibit tissue accumulation of AGEs in diabetes, including inhibitors of AGE formation such as aminoguanidine, ALT 946, and pyridoxamine-or putative cross-link breakers such as ALT 711. Alternative interventions have also included the administration of a soluble receptor for RAGE, sRAGE, thus capturing circulating AGEs and preventing them from binding to the cell-bound full-length receptor RAGE, thereby inhibiting the proinflammatory and profibrotic response following AGE-RAGE binding. In this review we summarize the evidence for such antiglycation therapies in retarding or delaying the development and progression of diabetes-associated atherosclerosis and renal disease while focusing on interventional strategies inhibiting AGE accumulation. In summary, all approaches have been shown to confer some degree of antiatherosclerotic and renoprotective effects, albeit to different degrees and by different mechanisms."R
  3. "[N]ovel therapeutic agents to reduce the accumulation of AGEs in diabetes have gained interest as potential cardioprotective approaches. A variety of agents have been developed which are examined in detail in this review. These include aminoguanidine, ALT-946, pyridoxamine, benfotiamine, OPB-9195, alagebrium chloride, N-phenacylthiazolium bromide and LR-90."R
  4. "The mechanism of action of PM includes: (i) inhibition of AGE formation by blocking oxidative degradation of the Amadori intermediate of the Maillard reaction; (ii) scavenging of toxic carbonyl products of glucose and lipid degradation; and (iii) trapping of reactive oxygen species. The combination of these multiple activities along with PM safety posture it as a promising drug candidate for treatment of diabetic complications as well as other multifactorial chronic conditions in which oxidative reactions and carbonyl compounds confer pathogenicity."R
  5. "This review summarizes current knowledge on the mechanism of formation of AGE/ALEs [Advanced Glycation Endproducts/Advanced Lipoxidation Endproducts], proposes a mechanism of action of PM, and summarizes the results of animal model studies on the use of PM for inhibiting AGE/ALE formation and development of complications of diabetes and hyperlipidemia."R

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