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Pyrroloquinoline quinone (PQQ) is known as a redox cofactor. It is similar to CoQ10 (CoEnzyme Q10) in the sense that it aids with oxidation and reduction reactions and associates itself with proteins, but rather than being located in the mitochondria's electron transport chain, PQQ is located in the cells cytoplasm and forms what is known as a 'water-soluble electron transport chain' (a non-legitimate term, used to demonstrate the point of PQQ conducting many REDOX reactions). It is amazingly potent at doing this, being able to conduct 1000-10,000 more REDOX cycles than the standard Vitamin C.
Depending on the context, it can act either as an anti-oxidant molecule by indirect means (inducing production of anti-oxidant enzymes) or it can act in a pro-oxidative manner; this pro-oxidative mechanism seems to underlie PQQ's effects in anti-cancer and perhaps anti-diabetic interactions, while anti-oxidative measures underlie the anti-inflammatory and cell protection pathways. It seems to moderate oxidation well, but there is not enough evidence in living animals and humans (in vivo evidence) to come to conclusions.
PQQ appears to, based on the preliminary evidence right now, be a potent producer of mitochondria and increase the energy capacity of a cell. Some animal studies suggest that increased mitochondria from PQQ are what underlies an observed increase in metabolic rate and reduction of triglycerides (from the metabolic rate, using fatty acids as fuel rather than having them stored or float around). It also appears to be neuroprotective, and the lone human study cited on Examine demonstrates improved sleep patterns in persons with disturbed sleep. Another human study touting a doubling of memory retention in the elderly given 20mg PQQ cannot have its primary source located online, despite being cited everywhere (Nakano et al.;Food Style 21 13 (7): 50–52. 2009) This aforementioned untracable study also claims 20mg PQQ is synergistic with 300mg CoQ10.
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Although benefit can be seen from dosages as low as 2mg a day (extrapolated from animal studies), limited studies in humans use 10-20mg daily which appears to also be used in supplement formulations.
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So I got the '50% boost in memory' study, and it turns out that this was never claimed; time to take a step back and realize that although PQQ is good it is preliminary and (in all honesty) this compound is being set up to be the next marketing CoQ10 in the sense that for every abstract unit of promise it exerts people will claim 10 abstract units of benefit that are not proven.
PQQ is being set up to be overmarketed to hell, it seems. Still has potential as an awesome molecules, but anything can be overmarketed
The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Pyrroloquinoline quinone has in your body, and how strong these effects are.
|Grade||Level of Evidence|
|A||Robust research conducted with repeated double blind clinical trials|
|B||Multiple studies where at least two are double-blind and placebo controlled|
|C||Single double blind study or multiple cohort studies|
|D||Uncontrolled or observational studies only|
|Level of Evidence ||Effect||Change||Magnitude of Effect Size ||Scientific Consensus||Comments|
A reduction in self-reported stress has been noted after 8 weeks in persons with self-reported sleep problems; this study also noted improvements in sleep
A decrease in fatigue has been noted in older adults with self-reported energy problems
An improvement in sleep quality has been noted in persons with impaired sleep; it is not certain how PQQ affects persons with normal sleep cycles
In persons with sleep disorders taking PQQ (which improved sleep) there were reductions in pain ratings at the end of the trial
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Pyrroloquinoline quinone (henceforth PQQ) is a heat stable, water soluble compound first identified in bacteria as an enzymatic cofactor. It is found naturally in most foods and herbs, with the highest sources being:
The overall range of content in foods according to one study appears to be 0.19ng/g or mL to 7.02ng/g fresh weight, or 3.7-61ng/g fresh weight, and other authors have criticized that measured numbers may be too low due to not measuring IPQ levels as well (a byproduct of PQQ which may be bioactive).
PQQ is present in a wide-variety of foods, but currently the estimates of its contents are quite variable. This may be due to confusions as to whether solely PQQ should be counted or PQQ conjugates (which it is not known if these confer dietary benefit)
Due to the involvement of PQQ in bacteria (from where it was discovered in 1979) and the involvement of quinoproteins in the fermentation process  (which PQQ associates with) and the above higher count of PQQ recorded in fermented foods; it is hypothesized that fermentation may increase PQQ content. Interestingly, common strains of bacteria in the human intestinal tract do not appear to synthesis much PQQ.
It should be noted that due to an affinity of PQQ to bind to amino acids and form imidazolopyrroloquinoline derivatives that the PQQ content of foods may not be the same as the total bioactive amounts of PQQ, probably due to rapid association with proteins forming amino acid conjugates (Imidazolopyrroloquinoline, or IPQ). Human milk, for example, contained 15% PQQ and 85% IPQ derivatives. That being said, no direct studies have been undertaken to see whether PQQ and IPQ have similar or different properties in vivo.
Pqq may form conjugates with dietary protein, but it is not known whether or not this possibility is bad, good, or inert
Pyrroloquinoline quinone is heat-stable and water soluble. As mentioned before, it is a relatively stable REDOX factor in vivo, and is able to carry generally around 20,000 REDOX reactions before degradation. In some in vitro studies, combining PQQ with reducing agents (SIN-1, sodium borohydride) can form a green precipitate.
PQQ is created in the human body at around 100-400 nanograms a day which some authors have claimed leads to a tissue concentration of approximately 0.8−5.9 ng/g in humans, this de novo synthesis is regulated by expression of a group of six genes named PqqA-F. Since complete deprivation from the diet of animals has been shown to hinder growth and reproductive performance, PQQ was initially claimed to be a vitamin in humans that proposed an enzyme (AASDH) as a PQQ-dependent enzyme in mammals, biological dependence is required for classification of a molecule as a vitamin. However, this enzyme was not solely PQQ dependent and PQQ cannot be classified as a dietary vitamin.
Pyrroloquinoline quinone does not have the status of a 'vitamin' although it shares properties similar to vitamins, and may be a 'vitamin-like compound' due to its presence in foods and biological effects
PQQ has been investigated for being a growth factor in youth, secondary to its effects at improving mitochondrial biogenesis (making more mitochondria) at seemingly effective doses of 0.2-0.3mg/kg foodstuff (in mice), which is surprisingly close to the levels found in human breast milk.
May be very beneficial for infants and youth, but more (any) human studie are needed
PQQ is used as a non-covalently linked ortho-quinone cofactor in REDOX reactions in the cell and oxidative deaminations and is made from the amino acids tyrosine and glutamate. It is seen as a novel REDOX catalyzing agent due to its stability, which prevents most self-oxidation (seen in catechins) and polymerization (tannins). A case has been made that PQQs effects are constant between species and bacteria, which aims to validate extrapolation from one species to humans. The potency of PQQ and its quinoproteins in REDOX cycling appears to be approximately 100-fold greater than Vitamin C or other polyphenolic compounds, when in alkaline conditions.
The proteins it works with tend to be groups of cellular proteins called quinoproteins, specifically glucose and alcohol dehydrogenases, as a cofactor. In bacteria, is seems to act as a trophic (growth) agent, and extends these properties to human mitochondria. One protein that exists in mammalians systems is known as 2-aminoadipic 6-semialdehyde dehydrogenase (or U26), with both adenosine monophosphate (AMP) and phosphopantetheine-binding binding domains, and six PQQ binding motifs. U26, however, does not have significantly altered mRNA translation of expression when comparing PQQ deficiency against PQQ supplemented rats nor do other enzymes associated with PQQ.
May work vicariously through stabilizing signalling proteins that belong to the class of quinoproteins, which then induce cascades in cell systems
PQQ seems to have good intestinal absorption and no long-term build-up in vital tissues (only skin).
PQQ has been implicated in preserving neuronal cells in the presence of glutamine-induced excitotoxicity. Mechanistically, activation of GSK-3β and Akt/PI3K has been noted as well as nuclear translocation and mRNA upregulation of Nrf2 which induces downstream HO-1 and Gamma-glutamylcysteine synthetase. The latter reactions of Nrf2 translocation and HO-1 induction are secondary to Akt/PI3K signalling, but abolishing this pathway does not completely abolish anti-oxidative defense in neurons but appears to mostly normalize the cell survival rates when glutamate is induced. Although PQQ can suppress the glutamate induced activation of JNK, blocking this does not appear to affect cell viability like PI3K/Akt does.
Another mechanisms of cell protection is on the level of the glutamate (NMDA) receptor, where receptor oxidation (at the redox modulatory suldhydrl site) by PQQ at 50uM can reduce the pro-excitatory effects of reducing agents, without affecting the current per se. Despite these neuroprotective effects being secondary to oxidative by-products, no decreased cell viability was noted even up to 200uM PQQ. This same mechanism may confer protection from seizures by not influencing baseline NMDA-mediated activity but controlling excessive activity while reducing oxidative damage caused from excessive glutamate signalling.
In vivo, 10-20mg/kg PQQ injections 30 minutes before neural ischemia was able to reduce infarct size from hypoxia in all rats fed 10mg/kg PQQ from 95+/-3.6% (control) to 68.8+/-10.4% (PQQ). This reduction in infarct size as also seen when PQQ was injected immediately after hypoxia, but to a less potent degree (rather than the aforementioned 37.6% reduction in size, it was only 18.5%).
General neuroprotective effects against excitotoxicity secondary to increasing cell survival through PI3K/Akt
When assessing the effects of PQQ on peroxynitrate (combination of nitric oxide and the superoxide radical), it does not appear to influence the toxicity of the molcule yet it reduces the formation thereof. When using SIN-1 as a way to produce peroxynitrate and induce cell death in vitro, PQQ at 100uM abolished cell death prior to peroxynitrate formation with an EC50 of 15+/-8.4uM, yet actually potentiated pre-existing peroxynitrate toxicity (also seen with superoxide dismutase, an anti-oxidant enzyme, when catalase was not present). The mechanism appears to be through sequestering the superoxide radical without significantly influencing nitric oxide, as PQQ does not appear to modify many parameters of nitric oxide or peroxynitrate per se yet potentiated a SIN-1 induction of cGMP and production of nitrate, theoretically caused by a backlog of nitric oxide that could not convert to peroxynitrate due to less free superoxide radicals. Interactions with PQQ and superoxide radicals has been noted previously.
Can prevent superoxide radical induced cell death, but does not significantly influence nitric oxide cell death per se
When injected into rats at 10mg/kg bodyweight, PQQ does not appear to cause overt behavioural changes in regards to sedation, activty, or heart rate with no alterations in EEG readings being observed.
Several morphological changes are associated with PQQ that may confer pro-cognitive effects, such as proliferation of Schwann cells secondary to PI3K/Akt activation, PQQ is also able to induce production of Nerve Growth Factor (NGF) secondary to COX induction; increases in NGF have been observed in vivo when using trimethylesters (for permeability into the brain) with a maximal increase of 1.7-fold over baseline associated with a PQQ metabolite named oxazopyrroloquinoline.
PQQ supplementation has also been associated with preventing stress-associated (oxidative stress mediated) declines in memory reducing damage done by methylmercury toxicity, and reducing memory impairment induced by a lack of oxygen; at 20mg/kg bodyweight PQQ has a potency nonsignificantly different than 200mg/kg Vitamin E (as R-R-R-Alpha tocopherol) in reversing age-related memory decline in rats. which, together with its neuroprotective status, assure it a position as a rehabilitative Nootropic.
Currently, one study has been conducted in humans using PQQ at 20mg daily or using PQQ at 20mg paired with 300mg CoQ10. This study used the supplements once-daily at breakfast for 12 weeks in persons aged 51.7-52.3yrs with the three tests being a Verbal Memory test (seven words read aloud and then asked to recite), the Stroop Test, and the CogHealth test. The results suggested a tendency towards improvement in the Verbal memory test (nonsignificant) a significant increase in performance in the Stroop test with PQQ+CoQ10 but not PQQ in isolation, and the choice reaction and simple reactions subsets of the CogHealth test showed statistically significant improvements with PQQ and PQQ+CoQ10 but the degree of improvement was not recorded.
General nootropic benefit for those with impaired cognitive function (due to age, neural damage, etc.) but does not have ample evidence to be claimed a cognition promoting nootropic in otherwise healthy. The one study conducted in humans does not claim a 50% or doubling of memory, and was not suited to answer this question
One open-label human study conducted with 20mg PQQ for 8 weeks in 17 persons with fatigue or sleep impairing disorder noted that PQQ was able to significantly improve sleep quality, with improvements in sleep duration and quality appearing at the first testing period 4 weeks after usage while a decrease in sleep latency required 8 weeks to reach significance. This study also noted improved appetite, obsession, and pain ratings that may have been secondary to improved sleep; contentness with life trended toward significance over 8 weeks but did not reach.
Truncated (more-so than full length) alpha-synuclein, a molecule similar to the beta-amyloid pigment associated with Alzheimer's, is a protein that has a high potential to accumulate and damage dopaminergic neurons and accelerate the pathology of Parkinson's Disease. PQQ, in a concentration dependent manner, inhibits formation of amyloid fibrin formation of both full length and truncated alpha-synuclein, and reduced the cytotoxicity of alpha-synuclein molecules in vitro. 280uM PQQ was able to reduce pre-existing fibrils by 14.8-50% depending on the structure of the alpha-syneclein molecule, and based on light scattering it appeared to prevent further aggregation.
A second mechanism by which PQQ may protect against Parkinsons is by reducing the toxicity of 6-hydroxydopamine, a toxic analogue of dopamine that is used in research to induce Parkinsons Disease yet is found in higher levels in the urine of persons with Parkinsons, suggesting it is more of a concern in these persons. Oxidative neurotoxicity and DNA fragmentation induced by 6-hydroxydopamine was reduced in a concentration dependent manner with concentrations of 0.3uM showing efficacy, yet this protective effect was not seen with Vitamin C or Vitamin E, two other anti-oxidants tested at concentrations up to 100uM.
Similar protective effects have been observed in vitro the pigment assocaited with Alzheimer's Disease, beta-amyloid, where PQQ incubation was able to reduce the cytotoxic effects of beta-amyloid on neuronal cells.
Appears to protect neuronal function from the adverse effects of the two aforementioned protein structures, which may confer therapeutic or preventative help to both Parkinson's and Alzheimer's Disease pending more research
Schwann cells (of the myelin sheath) have been shown to proliferate under PQQ incubation secondary to PI3K/Akt activation and can induce Nerve Growth Factor (NGF) in vitro, suggesting it may aid in nerve recovery.
In an animal study where physical damage was done to the sciatic nerve, a small amount of PQQ (10uL of 0.3mmol/L PQQ injections) accelerated functional recovery over a period of 12 weeks, and histolical observation noted a higher density of well-mylenated fibers in the PQQ group relative to control; these results have been replicated elsewhere using similar experimental techniques and similar results.
Has the ability to repair nerve structure and the Myelin Sheath, and has been observed to do so after injections into research animals (rats)
Protective effects have been noted in cardiac myocytes subject to ischemia, secondary to scavenging of peroxynitrate radicals, at injectible doses of 15mg/kg bodyweight 30 minutes prior to ischemia. PQQ was studied alongside metprolol as a combiantion anti-oxidant/beta-blocker therapy, and 3mg/kg PQQ and 1mg/kg metprolol were both insignificantly different in reducing mortality (40% of control passed, 8% of PQQ and 14% of metprolol) while no deaths were recorded in combination therapy. Combination was also more effective in reducing infarct size relative to either therapy in isolation, and both groups using PQQ had a reduction of creatine kinase release that was insignificantly different between groups.
The combination therapy study noted increased cardiac mitochondrial respiration with PQQ but neither metprolol nor PQQ+metprolol, and respiration was further increased even in the contrl groups with no ischemia/reperfusion done.
Secondary to the pro-mitochondrial effects and anti-oxidative effects during ischemia/reperfusion, PQQ appears to be cardioprotective under certain contexts
In rats fed a PQQ deficient diet relative to the same diet fed with 2mg/kg PQQ, plasma diglycerides and triglycerides (DAG and TAG) were elevated 20-50% (higher value related to triglycerides) in the PQQ deficient diet relative to 2mg/kg with no significant difference in free fatty acids, which is similar to levels previously seen with this experimental protocol. The elevation of triglycerides in the deficient mice does not influence the n3/n6 omega fatty acid ratios.
The increase seen in triglycerides may be due to this study being conducted for a long period of time, where previous research has demonstrated that PQQ deficient diets reduce mitochondrial density by 20-30% and levels of mRNA for PPAR, Fatty Acid binding protein, and Acyl CoA oxidase being significantly reduced with PQQ deficiency. Additionally, higher levels of beta-hydroxybutryic acid (indicative of less beta-oxidation) were seen in PQQ deficient rats. Inducing PQQ deficiency from a sufficient state can also elevate triglyceride levels to almost two-fold the previous levels, with the trend being reversed upon acute administration of PQQ in pharmacological amounts (2mg/kg bodyweight).
Appears to reduce triglycerides very potently (to a greater extent than Fish Oil, empirically) in research animals relative to a PQQ deficient diet, which can be used as evidence to either supplement or seek out PQQ containing foods due to the low amounts of PQQ needed for these effects. Secondary to increased mitochondrial density causing greater beta-oxidation of fatty acids
In young rats (before sexual maturation), PQQ either at 3mg/kg in the diet or having a PQQ deficient diet does not seem to significantly affect blood glucose or insulin levels. An increased glucose AUC was seen when PQQ deficient mice were subject to an oral glucose tolerance test, but no single time point was significnatly different. Injections of PQQ at 4.5mg/kg bodyweight also did not significantly influence blood sugar or insulin levels in healthy rats, but was able to significantly reduce glucose AUC (by 7%) and glucose disposition in diabetic rats fed glucose and injected with PQQ, with no effect of PQQ on fasting glucose levels in rats.
It has potential for alleviating fat-induced insulin resistance (characterized by a dysregulation in beta-oxidation of the TCA cycle) by increasing mitochondrial biogenesis in muscle cells, similar to exercise.
At this moment in time, nothing remarkable about PQQ and glucose metabolism
A study in rats comparing PQQ deficiency against PQQ sufficient diets (2mg/kg bodyweight) found that the decrease in liver mitochondrial mass over time was correlated with a decreased overall metabolic rate in the PQQ deficient rats, with a weak and almost non-existent correlation when looking at both fed and fasted (R=0.6) and a stronger correlation when only investigating fed state metabolic rate (R=0.9). Although the decrease in metabolic rate did not reach statistical significance, its magnitude approached the PQQ deficient group being at 90% the PQQ sufficient group.
No significant differences were seen in respiratory quotient, a marker of the percentage of energy derived from fatty acids or glucose.
A deficiency of PQQ, secondary to less mitochondria, may reduce overall metabolic rate and to a fairly noticeable degree (90% of baseline value, according to this study). Normalization of PQQ status normalizes this, but more evidence would be nice
PQQ appears to have some interactions with the immune system, as deprivation of PPQ from the diet (relative to a PQQ sufficient diet) appears to cause abnormal immune function in mice, with altered immune response after stressors.
A study on parental (intravenous) nutrition found that the addition of 3mcg PQQ to the parental nutrition in mice was able to increase the count of CD8+ cells and lymphocytes in intestinal Peyer's Patches, although not to the level of oral control.
Application of PQQ to macrophages in vitro was able to prevent osteoclast differentiation at doses as low as 0.1uM (but more potency at 10uM) secondary to increasing IFN-β secretion; IFNβ is a negative regulator of osteoclast differentiation normally released after inflammation, and PQQ increases its release (and subsequent suppression), which is also demonstrated by increased levels of proteins induced by IFN-β (iNOS, STAT1, JAK1). PQQ was found to phosphorylate nF-kB, p38, and IKKβ in these cells which is a pro-inflammatory response in macrophages.
Practical relevance unknown
PQQ has been shown to be cytotoxic to U937 leukemia cells, but not NIH3T3 nor L929 cells, in a dose-dependent manner. Catalase treatment neutralized these effects, as they appear to be secondary to hydrogen peroxide production in cells which PQQ has been repeatedly shown to induce. Superoxide dismutase had no effect on PQQ cytotoxicity, while glutathione or N-AcetylCysteine increased cytotoxicity 2-5fold without affecting the cells on their own (and thus working via PQQ by increasing H2O2 production form PQQ 1.5-2fold). PQQ by itself decreased intracellular glutathione levels, and when glutathione was depleted (via BSO, an inhibitor of γ-glutamylcysteine synthetase) the apoptosis of cells morphed into necrosis, and this necrosis was still mediated by H2O2 due to being inhibited by catalase.
Induces cell death via H2O2, and uses glutathoine to produce even more H2O2 to augment its efficacy. A depletion of glutathione induces necrosis
PQQ has been implicated in reducing melanogenic (melanin producing) protein expression in cultured B16 cells, where it can inhibit tyrosinase expression and reduce gene activity and can prevent stimulation of tryosinase mRNA by alpha-melanocyte stimulating hormone.
In a study done on rodents, introduction to a PQQ deficient diet for 10 weeks altered expression of 238 (out of about 10000 tested) genes and the transcription of 438, whereas repletion reversed these effects yet affected a total of 847 transcriptions. Those most affected were cellular stress (Thioredoxin) and mitochondrial biogenesis (PCG-1a) as well as the MAPK and JAK/STAT pathways of cell signalling and proliferation.
JAK/STAT and MAPK pathways (perhaps secondary to ILN-β?) and mitochondrial biogenesis secondary to Thioredoxin interactions appear to be the main locuses for PQQ's effects in the mammalian body
PQQ is an activator of the Peroxisome Proliferator Activating Receptor Gamma cofactor 1 alpha (PGC-1a) and thus regulates mitochondriogenesis in vivo. Activation of PGC1-a is also associated controlling blood pressure, regulating cellular cholesterol homeostasis, and the development of obesity and mitochondrial protection; direct human studies between PQQ supplementation and these topics have not been undertaken as of yet.
When studies are undertaken in rats comparing a PQQ deficient diet (and thus relying on de novo biogenesis) against PQQ sufficient diets, the PQQ supplemented diets tend to promote up to 20-30% more mitochondria in the liver (on a mass basis, as assessed by mtDNA) over the rats lifetime. Decreased permeability of the mitochondrial membrane has also been noted along with the mitochondrial count per cell increasing to 91+/-6.6 with 2mg/kg PQQ fed by gavage starting from 2 weeks of age in rats and 56.8+/-7.8 in PQQ deficient diets, although the actual size of each mitochondria did not differ (just count and functional capacity).
At least one animal study that did not induce a PQQ deficiency has noted that respiration (indicative of mitochondrial potential) was increased after PQQ administration to animals.
Supplementation of PQQ is associated with greater mitochondrial density, and deprivation induces a relative loss of mitochondria. Some studies note that supplementation above basal levels can further increase mitochondrial density in non-deficient mammals
One in vitro study using PQQ found that PQQ inhibited both glutathione reductase and thioredoxin reductase 1 (TrxR1); the isozyme present in human cytosols that is capable of reducing thioredoxin, a redox protein. PQQ appears to act as a low potency substrate for TrxR1 that outcompetes higher potency substrates in a reversible manner by binding to the Sec residue of TrxR1. By occupying this space, the affinity of TrxR1 towards substrate not dependent on Sec such as Juglone increases, and total NADPH oxidation (biomarker of TrxR1 activity) actually increases with 10-50uM PQQ due to thioredoxin not contributing to NADPH oxidation but instead a combined contribution of PQQ (low activity) and juglone, which has up to 12.67-fold increased activity possibly secondary to a lower Km of TrxR1 for juglone, which was 7.6uM without PQQ and 0.34uM with 50uM PQQ.
It has been demonstrated elsewhere that inhibition of TrxR1 causes an upregulation of Nrf2 (and subsequently, other effects in the cell) as TrxR1/Thioredoxin and Nrf2 are intimately linked with the latter's activity increasing when the former enzyme is abolished and Trx-related transcripts being some of the most affected genes following PQQ supplementation in rats. It is possible this inhibition signals the nucleus to transcribe anti-oxidant defense (as inhibition tends to co-exist with pro-oxidative states) despite the overall activity of TrxR1 not actually being hindered despite its selective inhibition towards thioredoxin.
May trick the cell into believing that a pro-oxidative state exists, by preventing Thioredoxin Reductase 1 (enzyme) from acting on Thioredoxin (substrate); causing the substrate to signal the nucleus to create anti-oxidative defenses to counter for the supposed pro-oxidative state while the enzyme merely changes substrate to a mix of PQQ and Juglone to maintain or enhance activity
PQQ has also been shown to inhibit glutathione reductase, but despite a decreased Km towards juglone (which would increase NAPDH oxidation and enzyme activity) the Kcat was also reduced and enzyme activity remains similar with or without PQQ. However, GSSG reduction with 5uM PQQ was reduced approximately 2-fold.
Another study noted that REDOX cycling of PQQ could produce hydrogen peroxide (H2O2), which after binding to the catalytic site (Cys-215) of PTP1B inhibited the functions of PTP1B and caused more growth in an A431 cell line via the EGFR receptor and subsequent ERK1/2 signalling to the nucleus and enhancing cell growth rate by up to 150% at 10-50uM or greater (depending on assay used); this mechanism is abolished by incubation with anti-oxidant catalase, dependent on ATP, and PQQ is not a ligand for EGFR.
PQQ has been shown to be cytotoxic to U937 leukemia cells, but not NIH3T3 nor L929 cells (but was observed in EL-4), in a dose-dependent manner with most significance at 20-50uM. Catalase treatment neutralized these effects, as they appear to be secondary to hydrogen peroxide production in cells which PQQ has been repeatedly shown to induce. Superoxide dismutase had no effect on PQQ cytotoxicity, while glutathione or N-AcetylCysteine increased cytotoxicity 2-5fold without affecting the cells on their own (and thus working via PQQ by increasing H2O2 production form PQQ 1.5-2fold). PQQ by itself decreased intracellular glutathione levels, and when glutathione was depleted (via BSO, an inhibitor of γ-glutamylcysteine synthetase) the apoptosis of cells morphed into necrosis, and this necrosis was still mediated by H2O2 due to being inhibited by catalase.
Glutathione can be increased by cysteine containing supplements including N-AcetylCysteine or Whey Protein
In cancer cells susceptible to PQQ's induction of H2O2, adding glutathione to the cell by consuming Cysteine-containing supplements can augment the efficacy of PQQ
PQQ has been associated with renal tubule inflammation at the dose of 11-12mg/kg bodyweight in rats after injections, and some symptoms of both renal and hepatic toxicity are seen with injections of 20mg/kg in rats. Acute death from PQQ injections between doses of 500-1000mg/kg bodyweight has been recorded in rats.
11-12mg/kg bodyweight, based on rudimentary body surface area conversions, is approximately 120-131mg/PQQ daily (although injections) if extrapolated to humans.
Chronic toxicity to the kidneys and liver may be achieved at a relatively low dose, although acute death requires a very high and unpractical dose. Until more evidence surfaces, it would be prudent to avoid superloading
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