![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 5 to 29 of 55. Go back in thread:
Posted by tealady on October 17, 2004, at 17:35:32
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on October 17, 2004, at 14:04:51
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1956581&dopt=Abstract
>
> "This BH4/DHPR-mediated antioxidation system is as effective as other antioxidation agents such as ascorbic acid, cysteine and reduced glutathione."
>There's that tetrahydrobiopterin (BH4) and also DHPR another opteridine. I think Ray takes biopterin? What is it ?
> I.e. keep your antioxidant supplies up (avoid oxidative stress). Make sure you take vitamin C, and selenium.
>
> > the radical superoxide can oxidise catecholamines too, so wonder whether depletion of dopamine by autoxidation can then change receptor sensitivity too?
>
> > http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2982420&dopt=Abstract.
>
> "Adrenaline oxidation was unaffected by the presence of exogenous linolenic acid or methylarachidonic acid, while arachidonic acid, with a Km for this reaction of 175 microM, showed a marked stimulatory effect. This activation was suppressed by superoxide dismutase, catalase and NaCN, while mannitol was without effect."
>
> I.e. shift the omega-6:omega-3 balance to reduce arichidonate release by phospholipase A2, and ensure adequate zinc and manganese to maintain SOD function.
>
> > and another...
> >http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8913362
>
> "N-acetylcysteine produced a dose-dependent decrease in dopamine-induced cell death; this correlated with a decrease in peroxide formation."
>
> NAC spares glutathione, so again, you have antioxidant defenses implicated, rather than the dopamine, IMHO.
>
> > the toxic quinones need to be detoxified by our friend glutathione!
> >
> > Ray
>
> Actually, glutathione et al keep them from forming in the first place.
>What do you think of these comments abou not taking NAC if you have amalgam fillings?
Some nutritional authorities recommend taking a form of cysteine known as N-acetyl-cysteine (NAC), but I would advise against using this supplement if you still have mercury amalgam fillings because it could interfere with the detoxification of the mercury. Personally I consume 300 mg of alpha lipoic acid and 5,000 mg of glutamine and 2,500 mg of vitamin C before I do my seven-mile run as I believe it will maximize the glutathione production to decrease the damage from the free radicals that I generate when I exercise. Controlling the damage from free radicals is one of the keys to slowing down the aging process.
http://www.mercola.com/2000/jun/24/sugar_glutathione.htm
>
> Oxidative stress plays havoc with your sulphur metabolism. So, cysteine, carnitine, taurine, glutathione, SAMe....many key molecules get trashed because sulphur gets trashed before carbon. The reason many antixidants have sulphur atoms is sacrificial. Selenium substitutes for sulphur to become even more sacrificial (as in seleno-cysteine). If there isn't enough sulphur to martyr itself on our behalf, other stuff gets mucked right up, or sulphur-bearing molecules we need for other purposes get destroyed instead.
>
What is the best way of geeting sulphur? Betaine? what form of betaine? TMG I think you used too take?? I'm putting an order in soon from O'd
seas.
Also
http://www.dr-bob.org/babble/alter/20040928/msgs/403607.html
end of post on my sulphur sensitivies..
I'm confused what this means I should do if I want to get my sulphur intake up.
I am trialing adding a little Epsom salts (like a small pinch) to a bottle of water at present.Maybe one day I'll understand a bit better <g>.
I'm doing one subject in Cell Biology this semester..next year 1st year Chem <g>.Jan
Posted by raybakes on October 21, 2004, at 5:04:44
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 17, 2004, at 14:34:12
Hi Lar,
found some more info on dopamine metabolism - find NADPH quinone oxidoreductase (NQO) of interest. From what I can make out, it seems that NQO reduces quinones to make them available for detoxification via sulphation or glucuronidation. One abstract talked about copper complexing with dopamine and inducing a neurotoxic reaction - NQO, inhibited this too.
On the mechanism of the Mn3(+)-induced neurotoxicity of dopamine:prevention of quinone-derived oxygen toxicity by DT diaphorase and superoxide dismutase.
Department of Biochemistry, University of Stockholm, Sweden.Dopamine (DA) is rapidly oxidized by Mn3(+)-pyrophosphate to its cyclized o-quinone (cDAoQ), a reaction which can be prevented by NADH, reduced glutathione (GSH) or ascorbic acid. The oxidation of DA by Mn3+, which appears to be irreversible, results in a decrease in the level of DA, but not in a formation of reactive oxygen species, since oxygen is neither consumed nor required in this reaction. The formation of cDAoQ can initiate the generation of superoxide radicals (O2-.) by reduction-oxidation cycling, i.e. one-electron reduction of the quinone by various NADH- or NADPH-dependent flavoproteins to the semiquinone (QH.), which is readily reoxidized by O2 with the concomitant formation of O2-.. This mechanism is believed to underly the cytotoxicity of many quinones. Two-electron reduction of cDAoQ to the hydroquinone can be catalyzed by the flavoprotein DT diaphorase (NAD(P)H:quinone oxidoreductase). This enzyme efficiently maintains DA quinone in its fully reduced state, although some reoxidation of the hydroquinone (QH2) is observed (QH2 + O2----QH. + O2-. + H+; QH. + O2----Q + O2-.). In the presence of Mn3+, generated from Mn2+ by O2-. (Mn2+ + 2H+ + O2-.----Mn3+ + H2O2) formed during the autoxidation of DA hydroquinone, the rate of autoxidation is increased dramatically as is the formation of H2O2. Furthermore, cDAoQ is no longer fully reduced and the steady-state ratio between the hydroquinone and the quinone is dependent on the amount of DT diaphorase present. The generation of Mn3+ is inhibited by superoxide dismutase (SOD), which catalyzes the disproportionation of O2-. to H2O2 and O2. It is noteworthy that addition of SOD does not only result in a decrease in the amount of H2O2 formed during the regeneration of Mn3+, but, in fact, prevents H2O2 formation. Furthermore, in the presence of this enzyme the consumption of O2 is low, as is the oxidation of NADH, due to autoxidation of the hydroquinone, and the cyclized DA o-quinone is found to be fully reduced. These observations can be explained by the newly-discovered role of SOD as a superoxide:semiquinone (QH.) oxidoreductase catalyzing the following reaction: O2-. + QH. + 2H+----QH2 + O2. Thus, the combination of DT diaphorase and SOD is an efficient system for maintaining cDAoQ in its fully reduced state, a prerequisite for detoxication of the quinone by conjugation with sulfate or glucuronic acid. In addition, only minute amounts of reactive oxygen species will be formed, i.e. by the generation of O2-., which through disproportionation to H2O2 and further reduction by ferrous ions can be converted to the hydroxyl radical (OH.). Absence or low levels of these enzymes may create an oxidative stress on the cell and thereby initiate events leading to cell death.
Drug treatment of Parkinson's disease. Time for phase II.
Department of Neurology, Research Institute Neurosciences, Vrije Universiteit, 1081 BT, Amsterdam, The Netherlands.Parkinson's disease (PD) is a neurodegenerative syndrome for which at present no cure is available; therapy consists mainly of amelioration of the symptoms with L-Dopa and/or dopamine (DA) agonists. Development of an effective causal therapy should be focussed on preventing or at least retarding the neurodegenerative process underlying the disease. At the cellular level, PD is characterized by degeneration of neuromelanin-containing dopaminergic neurons in the substantia nigra. Neuromelanin formation is the outcome of a process generally known as DA autooxidation, a chain of oxidation reactions in which highly neurotoxic DA-quinones are produced. The level of these DA-quinones, as estimated by the occurrence of their cysteinyl conjugates, is reported to be increased in the Parkinsonian substantia nigra. Hence, stimulation of pathways implicated in the detoxication of DA-quinones in the brain may provide neuroprotection in PD. Besides their inactivation through non-enzymatic antioxidants such as ascorbic acid and glutathione, DA-quinones are efficiently inactivated enzymatically by NAD(P)H:quinone oxidoreductase (NQO) and glutathione transferase(s), both of which are expressed in the human substantia nigra. The activity of these enzymes, which belong to the group of phase II biotransformation enzymes, can be up-regulated by a large variety of compounds. These compounds, including dithiolethiones, phenolic anti-oxidants, and isothiocyanates, have been shown to be active both in vitro and in vivo. Thus, considering the role of phase II biotransformation enzymes, in particular NQO and glutathione transferase(s), in the detoxication of DA-quinones, we propose that phase II enzyme inducers warrant evaluation on their neuroprotective potential in PD.
Ray
Posted by Larry Hoover on October 29, 2004, at 9:11:55
In reply to Re: dopamine oxidation » raybakes, posted by raybakes on October 21, 2004, at 5:04:44
> Hi Lar,
>
> found some more info on dopamine metabolism - find NADPH quinone oxidoreductase (NQO) of interest. From what I can make out, it seems that NQO reduces quinones to make them available for detoxification via sulphation or glucuronidation. One abstract talked about copper complexing with dopamine and inducing a neurotoxic reaction - NQO, inhibited this too.I once saw the most amazing "map" of all the reactions/pathways that tyrosine went through. I think it was tyrosine.....anyway, I think there were something like 800 products, intermediates, etc.
One can focus too much on a single tree, and forget that one is in a forest at all.
My "takehome message", the component in these articles that most catches my attention, is the link to the neuroprotective effects of those workhorse antioxidant systems. They have a limited capacity, a threshold of capability, beyond which neurotoxic effects can proceed unhindered.
The core dysfunction in numerous disorders, symptom clusters that differ in expression in different people, is oxidative stress. Antioxidants are sacrificial. They quench a highly reactive species by laying down their lives to protect the lives of others (in a personified expression). They consume chemical bullets by getting between the gun and the innocent target. What goes wrong when a bullet hits the target is illustrative of why we need to ensure a depth of reserve combatants. We preclude the need to examine the sequelae if we block the bullet before it reaches the target.
Lar
Posted by raybakes on October 29, 2004, at 13:20:59
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on October 29, 2004, at 9:11:55
> The core dysfunction in numerous disorders, symptom clusters that differ in expression in different people, is oxidative stress. Antioxidants are sacrificial. They quench a highly reactive species by laying down their lives to protect the lives of others (in a personified expression). They consume chemical bullets by getting between the gun and the innocent target. What goes wrong when a bullet
hits the target is illustrative of why we need to ensure a depth of reserve combatants. We preclude the need to examine the sequelae if we block the bullet before it reaches the target.
Thanks Lar, think we see things differently!! from my view, yes ideally we should have enough antioxidant troops to block the bullets, but what if we're in an autoimmune war zone with no end in sight....and to make matters worse our own troops are firing depleted superoxide bullets at our own dopamine and serotonin bases!Dr Hastings seems to be researching this line of thought (if you look carefully, she's got a flak jacket under her dress!)
http://www.pitt.edu/~neurosci/hastings.html
Genetically i have high interleukin 1 and low glutathione (null gene), so I'm predisposed to autoimmune disease - for me the autoxidation of catecholamines and serotonin is real, even with heavy intake of antioxdants - the research on quinones and kynurenine strikes a chord with me so I want to check it out and see if supporting that area helps my symptoms. I'm thinking of getting a urine organic acid test to see if there are any high levels of toxic neurotransmitter metabolites - have you had your's checked out, or can you recommend any tests?
Thanks, sorry about the dodgy metaphors!!
Ray
Posted by TeeJay on October 29, 2004, at 21:03:25
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 29, 2004, at 13:20:59
Ray
am I right in remembering you are an englishman? If so, where roughly in the country are you from? (i'm from the west midlands)
Also, where do you get your tests done?
Cheers
TJ
Posted by Larry Hoover on October 30, 2004, at 8:27:39
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 29, 2004, at 13:20:59
> Genetically i have high interleukin 1 and low glutathione (null gene), so I'm predisposed to autoimmune disease -
Ray, I'm very sorry. I didn't know that. I couldn't sleep last night, thinking about this. Please accept my apology. If you mentioned this before, I didn't see it, or don't recall it. All my opinions have been expressed under the assumptions that generally hold true. I didn't know you were the exception. How did you find out about the glutathione problem? And isn't IL-1 a response to oxidative stressors?
My intuitive response is for you to try and determine an exogenous antioxidant which has similar properties to that of glutathione. Frankly, I did not ever consider the ramifications of innate glutathione deficiency.
I'm immediately thinking of alphalipoic acid, and the polyphenolic antioxidants seen in e.g. pine bark or grape seed or berries. It would be lovely if someone ever put out a Venn diagram of the overlap between substrate activity of the different antioxidant systems. It would make this whole topic so very much easier to understand and to find appropriate interventions. I would need to look around a bit before I could come up with ideas not based on my intellectual intuition.
The other route would be immune modulation, as by omega-3 supplementation. Membrane disturbance induces degradation of phospholipids at the second position by phospholipase A2. You want an omega-3 fatty acid there, as much as is possible, to prevent inflammatory induction via cyclization of arachinodate to PGE-2.
> for me the autoxidation of catecholamines and serotonin is real, even with heavy intake of antioxdants - the research on quinones and kynurenine strikes a chord with me so I want to check it out and see if supporting that area helps my symptoms.
What antioxidants are you presently using?
> I'm thinking of getting a urine organic acid test to see if there are any high levels of toxic neurotransmitter metabolites - have you had your's checked out, or can you recommend any tests?
No. I'm fumbling in the dark, totally. I have trouble getting the simplest of blood or urine chemistries authorized, and I can't afford to pay for them myself. The vicious circle of poor health has got its grips in me. Poor health ---> can't work (much)---> can't afford assessment and treatment ---> poor health.
> Thanks, sorry about the dodgy metaphors!!
>
> RayAaaaccckkkk! Nothing we can't sort out.
Lar
Posted by raybakes on October 31, 2004, at 3:45:56
In reply to Re: dopamine oxidation » raybakes, posted by TeeJay on October 29, 2004, at 21:03:25
> Ray
>
> am I right in remembering you are an englishman? If so, where roughly in the country are you from? (i'm from the west midlands)
>
> Also, where do you get your tests done?
>
> CheersHi TJ, yes I live in Surrey. Got the gene tests done by great smokies via a british agent, called diagnostic sevices. Say hello to the black country - was in wolverhampton last month to watch some speedway - the wolves lost :(
Ray
Posted by raybakes on October 31, 2004, at 3:57:54
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on October 30, 2004, at 8:27:39
> > Genetically i have high interleukin 1 and low glutathione (null gene), so I'm predisposed to autoimmune disease -
>
> Ray, I'm very sorry. I didn't know that. I couldn't sleep last night, thinking about this. Please accept my apology. If you mentioned this before, I didn't see it, or don't recall it. All my opinions have been expressed under the assumptions that generally hold true. I didn't know you were the exception. How did you find out about the glutathione problem? And isn't IL-1 a response to oxidative stressors?That's OK Larry! The gene tests were from great smokies - I do have a couple of glutathione genes but have one that is a null gene.
Yes oxidative stress is a major factor in Il-1 release and as you say, PLA2 is a big problem - I do take max DHA by Jarrow, but some research says that pure EPA is a better inhibitor of PLA2.
I'm interested in the caspases, that are releasing enzymes for the interleukins, and how mitochondrial damage can set neuronal apoptosis into action - interestingly, glutathione and creatine, inhibit caspases.
Got to go to work now, so will reply more in full later - thanks for your concern!! hope you didn't lose too much sleep!!!
Ray
Posted by TeeJay on October 31, 2004, at 6:33:29
In reply to Re: dopamine oxidation » TeeJay, posted by raybakes on October 31, 2004, at 3:45:56
Thanks for the reply Ray,
When I was younger my dad used to take me every week to watch the Birmingham Brummies. They used to beat wolves refularly too ;-)))
Posted by raybakes on October 31, 2004, at 14:11:02
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on October 30, 2004, at 8:27:39
> I'm immediately thinking of alphalipoic acid, and the polyphenolic antioxidants seen in e.g. pine bark or grape seed or berries. It would be lovely if someone ever put out a Venn diagram of the overlap between substrate activity of the different antioxidant systems. It would make this whole topic so very much easier to understand and to find appropriate interventions. I would need to look around a bit before I could come up with ideas not based on my intellectual intuition.
I do take a lipoic acid and thiamine combination - i feel awful if I take them individually - wonder whether it's due to a balance in the pyruvate dehyrogenase complex? Sometimes take 'proanthanol' from allergy research, but doing really well on jarrow's pomegranate concentrate at the moment - adore organic raspberries too!
>
> The other route would be immune modulation, as by omega-3 supplementation. Membrane disturbance induces degradation of phospholipids at the second position by phospholipase A2. You want an omega-3 fatty acid there, as much as is possible, to prevent inflammatory induction via cyclization of arachinodate to PGE-2.Interleukin 1 stimulates PLA2 unfortunately! Grrr! Take phospatidyl choline every now and then as well as omega 3s - and I think all the methyl factors I take probably assist phospholipid synthesis.
.
>
> What antioxidants are you presently using?thiodox and thorne's extra nutrient complex are the one's I use most - can only get on with small amounts of ascorbate - think high doses might use up too much glutathione? The get the most relief from the methyl factors though - as long as I avoid molybdenum - don't think activation of oxidase enzymes agrees with me!
Ray
Posted by joebob on November 2, 2004, at 9:24:27
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 31, 2004, at 14:11:02
the extra cost?
there's a lot of talk about it at the moment
Posted by Larry Hoover on November 2, 2004, at 9:28:34
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 31, 2004, at 3:57:54
> > > Genetically i have high interleukin 1 and low glutathione (null gene), so I'm predisposed to autoimmune disease -
> >
> >How did you find out about the glutathione problem? And isn't IL-1 a response to oxidative stressors?
>
> That's OK Larry! The gene tests were from great smokies - I do have a couple of glutathione genes but have one that is a null gene.That redundancy is probably keeping you safe.
> Yes oxidative stress is a major factor in Il-1 release and as you say, PLA2 is a big problem - I do take max DHA by Jarrow, but some research says that pure EPA is a better inhibitor of PLA2.
Yes, but. The 2 in PLA2 is a positional specificity of the phospholipid hydrolysis. Whatever fatty acid is hanging there gets freed, and it is most likely to get cyclized. The eicosanoids arising from EPA do have that specific inhibitory effect, but as I understand it, the release of DHA from that position goes on to modulate gene expression. EPA has an acute suppressive effect, whereas DHA has a chronic down-regulatory effect.
http://www.pubmedcentral.gov/articlerender.fcgi?artid=122397Look at Table 5.
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=208755
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=139963
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=149905
> I'm interested in the caspases, that are releasing enzymes for the interleukins, and how mitochondrial damage can set neuronal apoptosis into action - interestingly, glutathione and creatine, inhibit caspases.
>
> Got to go to work now, so will reply more in full later - thanks for your concern!! hope you didn't lose too much sleep!!!
>
> RayBrain hum, Ray. I get involved....no, INVOLVED.
Lar
Posted by Larry Hoover on November 2, 2004, at 9:30:51
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on October 31, 2004, at 14:11:02
> thiodox and thorne's extra nutrient complex are the one's I use most - can only get on with small amounts of ascorbate - think high doses might use up too much glutathione? The get the most relief from the methyl factors though - as long as I avoid molybdenum - don't think activation of oxidase enzymes agrees with me!
>
> RayAm I wrong to think that high glutathione burden due to ascorbate might indicate that you are consuming the ascorbate, i.e. you need it?
Lar
Posted by raybakes on November 3, 2004, at 14:15:25
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 2, 2004, at 9:30:51
>
> Am I wrong to think that high glutathione burden due to ascorbate might indicate that you are consuming the ascorbate, i.e. you need it?
>
Thanks Lar for the EPA/DHA abstracts...and thanks being involved!!My thoughts were that severe brian fogging I get with high dose ascorbate might be using up too much glutathione for me and causing excess production of the ascorbyl radical? This article suggests it might be possible.
"For example, after vitamin C donates an electron to a free radical, it becomes what is known as the ascorbyl radical. The antioxidant known as reduced glutathione can restore ascorbyl radical to the antioxidant form of vitamin C."
Ray
Posted by tealady on November 3, 2004, at 21:49:24
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 3, 2004, at 14:15:25
I dn't do well on higher doses onf VitC either. Only use on rare occasions
I suspect I'm very low on glutathione too due to the foods I prefer.
Jan
Posted by Larry Hoover on November 4, 2004, at 11:02:03
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 3, 2004, at 14:15:25
>
> >
> > Am I wrong to think that high glutathione burden due to ascorbate might indicate that you are consuming the ascorbate, i.e. you need it?
> >
>
> Thanks Lar for the EPA/DHA abstracts...and thanks being involved!!You're welcome. In case you didn't realize, PMC is only full-text articles. Sometimes, if you're lucky, there will be hotlinks in the references that get you "inside" fee-based journals without having to pay. If that happens, don't save the link. It won't work later. Instead, email the article to yourself.
> My thoughts were that severe brian fogging I get with high dose ascorbate might be using up too much glutathione for me and causing excess production of the ascorbyl radical? This article suggests it might be possible.
>
> "For example, after vitamin C donates an electron to a free radical, it becomes what is known as the ascorbyl radical. The antioxidant known as reduced glutathione can restore ascorbyl radical to the antioxidant form of vitamin C."
>
> RayThe key term in the above exchange is that vitamin C donates an electron to a free radical. What that does is it stabilizes that free radical, so it can no longer participate in chain reactions. (As an aside, the ozone depletion in the atmosphere is caused by free radical chain reactions.)
The ascorbyl radical can then participate in chain reactions, but it is less reactive than the originating free radical. Glutathione quenches the ascorbyl radical, but is itself now a radical. There are a few processes by which glutathione is regenerated, and one of those is via alphalipoic acid.
There are lots of free radials running around in your body. Some of them are astoundingly dangerous, in a chemical sense, like superoxide. Antioxidants are sacrificial (they are used up), but in the process they become somewhat dangerous themselves. Just less dangerous. Antioxidants are best thought of as a network, because they interact and "rearrange" the reactivity.
One of the most common free radicals in the body is molecular oxygen. Although it's often represented as double-bonded, i.e. O=O, it doesn't stay like that. It resonates to the diradical form, represented as ·O-O· The dots represent unpaired electrons, called radicals. Molecular oxygen is so reactive that it can turn solid iron to powder (rust). Our bodies have evolved haemoglobin molecules to bind free molecular oxygen to iron atoms without oxidizing it permanently. This safely carries oxygen through the body without allowing its free radical character access to sensitive molecules. Oxygen is wicked dangerous, from a chemical perspective. Superoxide (O2-) cannot form a stable resonance structure, so it remains an oxygen free radical until it finds something to react with. It's all about stabilizing oxygen.....that's what life is all about.
Lar
Posted by raybakes on November 7, 2004, at 5:06:24
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 4, 2004, at 11:02:03
> The ascorbyl radical can then participate in chain reactions, but it is less reactive than the originating free radical. Glutathione quenches the ascorbyl radical, but is itself now a radical. There are a few processes by which glutathione is regenerated, and one of those is via alphalipoic acid.
>
>
Hi Lar,I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.
I understand the outline that you give about how all the antioxidant systems working in concert produce radicals or become radicals in the process of dealing with a free radical, but matching how I feel to what you say, there must be something else going on. I feel my antioxidant system is extremely fragile, and can probably only work at a certain rate - It probably has a few weak links in the chain - enzymes that when pushed too hard, run out of co-factors (NADPH to reduce glutathione is a suspect, particularly because it requires energy, something my brain lacks!).
So ascorbate could produce more ascorbyl radicals than glutathione could mop up before I started running low on NADPH. With NADPH running low, hydrogen ions build up in the cell, the pH drops, all enzymes fail, and I end up with millions more free radicals that I started with!
Just a theory, but that's how it sort of feels!
Ray
Posted by Larry Hoover on November 7, 2004, at 11:07:11
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 7, 2004, at 5:06:24
>
> > The ascorbyl radical can then participate in chain reactions, but it is less reactive than the originating free radical. Glutathione quenches the ascorbyl radical, but is itself now a radical. There are a few processes by which glutathione is regenerated, and one of those is via alphalipoic acid.
> >
> >
> Hi Lar,
>
> I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.Maybe that's the magnesium "talking"?
> I understand the outline that you give about how all the antioxidant systems working in concert produce radicals or become radicals in the process of dealing with a free radical, but matching how I feel to what you say, there must be something else going on.
I looked at the toxicity of vitamin C, and two possible mechanisms come to mind. One involves iron toxicity, exacerbated by the activation by ascorbate. Those with hemochromatosis are particularly vulnerable to this effect. The other mechanism involves enhanced excretion of uric acid. That might leave one vulnerable to peroxynitrite, as uric acid is an excellent peroxynitrite scavenger.
> I feel my antioxidant system is extremely fragile, and can probably only work at a certain rate - It probably has a few weak links in the chain - enzymes that when pushed too hard, run out of co-factors (NADPH to reduce glutathione is a suspect, particularly because it requires energy, something my brain lacks!).
You're the expert on how things make you feel, Ray. All I can do is offer you knew thoughts to try on for size.
> So ascorbate could produce more ascorbyl radicals than glutathione could mop up before I started running low on NADPH. With NADPH running low, hydrogen ions build up in the cell, the pH drops, all enzymes fail, and I end up with millions more free radicals that I started with!
I really doubt there's a pH mechanism at play. There are many many ways for cells to adjust pH. There are substantial buffer systems in place, just for that purpose. Do you understand the chemistry of buffer systems?
> Just a theory, but that's how it sort of feels!
>
> RayTry a different source of ascorbate, would be my suggestion.
Lar
Posted by raybakes on November 8, 2004, at 3:16:07
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 7, 2004, at 11:07:11
> > I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.
>
> Maybe that's the magnesium "talking"?Don't think so, feel great on magnesium malate/citrate.
>
> I looked at the toxicity of vitamin C, and two possible mechanisms come to mind. One involves iron toxicity, exacerbated by the activation by ascorbate. Those with hemochromatosis are particularly vulnerable to this effect....cytochrome c seems to be invoved in moppping up peroxynitrite interestingly..
The other mechanism involves enhanced excretion of uric acid. That might leave one vulnerable to peroxynitrite, as uric acid is an excellent peroxynitrite scavenger.
I definitely think peroxynitrite is a problem and uric acid is interesting....
> You're the expert on how things make you feel, Ray. All I can do is offer you knew thoughts to try on for size.Thanks for your thoughts and ideas but I don't want to make my self sound too badly off - I'm feeling pretty good these days, in fact the best I've felt for 10 - 20 years!
>
> > So ascorbate could produce more ascorbyl radicals than glutathione could mop up before I started running low on NADPH. With NADPH running low, hydrogen ions build up in the cell, the pH drops, all enzymes fail, and I end up with millions more free radicals that I started with!
>
> I really doubt there's a pH mechanism at play. There are many many ways for cells to adjust pH. There are substantial buffer systems in place, just for that purpose. Do you understand the chemistry of buffer systems?I don't understand all the buffer systems but suspect the bicarbonate buffering to be underfunctioning. If I raise carbon dioxide by holding my breath, or drinking carbonated water, my brain becomes more clear. Might be something to do with the bohr effect too? Also I think it's common in autoimmune disease to have antibodies to carbonic anhydrase, vital for bicarbonate buffering and digestive function. Bicarbonate seems to have both positive and negative effects on peroxynitrite - some abstracts say it helps detoxify it, some say it hinders uric acid, ascorbate, GSH in it's detoxification.
Found this abstract on how carbonic anhydrase is invovled in helping produce the cerebrospinal fluid, and it thought to influence 'neuroexcitation'.'Carbonic anhydrase IV on brain capillary endothelial cells: a marker associated with the blood-brain barrier.'
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1495971&dopt=Abstract
Still think buffering is really important - especially as in fatigued cells, the mitochondria fail to get sufficient numbers of protons combining with oxygen to maintain an even pH.Ray
> Try a different source of ascorbate, would be my suggestion.
I've tried about 8 or 9 types of ascorbate - all work really well as long as I stay below a gramme.
>
Posted by Larry Hoover on November 8, 2004, at 11:09:03
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 8, 2004, at 3:16:07
> > > I can only tell you what if feels like - I think high dose ascorbate would be fine with someone with normal health. I know if I take over 1 gramme of magensium ascorbate, I feel incredibly ill, mentally.
> >
> > Maybe that's the magnesium "talking"?
>
> Don't think so, feel great on magnesium malate/citrate.Okay. <shrug>
> > I really doubt there's a pH mechanism at play. There are many many ways for cells to adjust pH. There are substantial buffer systems in place, just for that purpose. Do you understand the chemistry of buffer systems?
>
> I don't understand all the buffer systems but suspect the bicarbonate buffering to be underfunctioning.That would be quite a stretch. Every breath you take is part of a feedback loop to the partial pressure of carbon dioxide in the blood.
Here's a good overview.
http://www.cvm.okstate.edu/courses/vmed5412/14%20Acid-Base.docWithin cells, the bicarbonate buffer is replaced by protein/amino acid buffers, and phosphate buffering. The latter buffer is what makes those lime scale/iron stain removers powerful enough to remove deposits on e.g. bathroom fixtures, but moderate enough that you can get them on your hands without fear.
> If I raise carbon dioxide by holding my breath, or drinking carbonated water, my brain becomes more clear. Might be something to do with the bohr effect too?
Almost certainly it is the Bohr effect. Not much more than a parlor trick, though, as you will breath again and restore the normal chemistry.
> Also I think it's common in autoimmune disease to have antibodies to carbonic anhydrase, vital for bicarbonate buffering and digestive function.
It seems to have a vital role in the transfer of oxygen to and from hemoglobin, among other effects. Carbonic anhydrase, in the presence of CO2, will facilitate the "unloading" of O2 from hemoglobin, while simultaneously replacing the O2 with H+ and bicarbonate. Each of the latter will then interact with the aqueous component of blood.
> Bicarbonate seems to have both positive and negative effects on peroxynitrite - some abstracts say it helps detoxify it, some say it hinders uric acid, ascorbate, GSH in it's detoxification.
Yes, but....
Bicarbonate is everywhere in your circulation, so whether it tips this balance a certain way, and that one another, is moot.
>
> Found this abstract on how carbonic anhydrase is invovled in helping produce the cerebrospinal fluid, and it thought to influence 'neuroexcitation'.
>
> 'Carbonic anhydrase IV on brain capillary endothelial cells: a marker associated with the blood-brain barrier.'
>
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1495971&dopt=AbstractWhen I read that, I see that a specific form of carbonic anhydrase is responsible for facilitating gas transfer at the capillary wall in the brain, i.e. at the blood-brain barrier. Red blood cells can't get across, so the unloading occurs at this membrane surface. Diffusion probably takes the 02 to the mitochondria.
> Still think buffering is really important - especially as in fatigued cells, the mitochondria fail to get sufficient numbers of protons combining with oxygen to maintain an even pH.
>
> RayOnly in extreme circumstances. That's what buffers do....maintain supplies of H+ without changing pH dramatically.
http://www.sparknotes.com/chemistry/acidsbases/buffers/section1.html
Lar
Posted by raybakes on November 8, 2004, at 13:55:57
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 8, 2004, at 11:09:03
>
> Only in extreme circumstances. That's what buffers do....maintain supplies of H+ without changing pH dramatically.
>
Thanks Lar, but I do think chronic fatigue and nervous system disorders are extreme circumstances - In nervous system disorders, mitochondrial failure surely means an accumulation of protons in the cell, lowering pH. How can a buffer system keep up when the only energy production in the cell is anaerobic?Ray
Posted by Larry Hoover on November 9, 2004, at 15:35:57
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 8, 2004, at 13:55:57
> >
> > Only in extreme circumstances. That's what buffers do....maintain supplies of H+ without changing pH dramatically.
> >
>
> Thanks Lar, but I do think chronic fatigue and nervous system disorders are extreme circumstances - In nervous system disorders, mitochondrial failure surely means an accumulation of protons in the cell, lowering pH. How can a buffer system keep up when the only energy production in the cell is anaerobic?
>
> RayRay, I fear we're far apart on our theoretical underpinnings. Or perhaps I'm just not grasping the unique character of a particular form of dysfunction you're trying to address.
Here's a pretty good summary of what goes wrong, IMHO (before it slides into the promotion of particular propietary remedies). http://www.immunesupport.com/library/showarticle.cfm/ID/4535/
The key is electron transport defects. Protonation (the hydrogen ion) is tightly controlled because of the high amine content in proteins (amines love to mop up protons), and because of the phosphate buffer.
Mitochondrial failure is associated with ROS (reactive oxygen species) at levels which overwhelm antioxidant defenses. Despite the failure of the mitochondrial membranes, stimulatory signals are still received by the mitochondria, which churn out ROS unhindered.
Anaerobic metabolism is extra-mitochondrial. It occurs in cell cytoplasm, and is very inefficient. Large amounts of "partially spent" molecules accumulate, the gross debris of inefficiency. Those include lactic acid, which is responsible for pain and spasm in over-exerted muscle, for example. But that is not a chronic state. Well, if it is, you're in big trouble, and you're likely in the ICU already.
If I've not grasped something you're putting forth, I'd really appreciate it if you'd spend some time with it, and lay it out for me anew.
Thanks,
Lar
Posted by raybakes on November 11, 2004, at 5:06:01
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 9, 2004, at 15:35:57
Hi Larry,
I've been reading abstracts like this one recently, and maybe it's explains why we don't see things in a similar way? The article you attached, talks of the accumulation of lactic acid causing fatigue in a cell, whereas the articles I've been reading talk of lactic acid being produced to reduce cellular acidosis.
Biochemistry of exercise-induced metabolic acidosis.
'When the ATP demand of muscle contraction is met by mitochondrial respiration, there is no proton accumulation in the cell, as protons are used by the mitochondria for oxidative phosphorylation and to maintain the proton gradient in the intermembranous space'
My interest is regarding my own brain fog, because if I improve buffering and support my mitochondria, my symtoms dramatically improve.
Found this abstract on creatine as well..
http://physrev.physiology.org/cgi/content/short/80/3/1107
'Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr and Cr analogs such as cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage'
Ray
Posted by Larry Hoover on November 11, 2004, at 10:56:35
In reply to Re: dopamine oxidation » Larry Hoover, posted by raybakes on November 11, 2004, at 5:06:01
> Hi Larry,
OK, you bum, you made me get out my textbooks.
> I've been reading abstracts like this one recently, and maybe it's explains why we don't see things in a similar way? The article you attached, talks of the accumulation of lactic acid causing fatigue in a cell,
Right. Lactic acid causes muscle cells to register what we know as fatigue, by some unknown signalling method. Lactic acid accumulates to keep pyruvate from increasing to toxic levels from glycolysis. Glycolysis is anaerobic (doesn't require oxygen), consumes 2 ATP, produces 4 ATP, converts 2 NAD+ to NADH, releasing 2 protons, and 2 pyruvate. That is the source of the acid stress. 2 pyruvate can produce 2 lactate, but in the process, 2 NADH are changed back to NAD+, consuming 2 protons. Lactic acid accumulation is a measure of compensatory response to excess formation of pyruvate. Only if pyruvate is in excess is lactate produced. There is no net release of protons from lactate production. You end up with 2 ATP from each glucose molecule, but respiration dead ends at lactate. Lactate is readily exported from the cell, but it is really a marker for excess pyruvate. Circulating lactate is at least partially reconverted to glucose in the liver (at the expense of ATP, of course). Proton stress is proportional to pyruvate production via glycolysis.
> whereas the articles I've been reading talk of lactic acid being produced to reduce cellular acidosis.
>
> Biochemistry of exercise-induced metabolic acidosis.
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15308499
>
> 'When the ATP demand of muscle contraction is met by mitochondrial respiration, there is no proton accumulation in the cell, as protons are used by the mitochondria for oxidative phosphorylation and to maintain the proton gradient in the intermembranous space'It would also be just as true to say that there is also no pyruvate accumulation in the cell, under normal respiratory conditions. Under excess anaerobic ATP production via glycolysis, the net accumulation in the cytosol from one glucose is 2 pyruvate, 2 protons (H+), and 2NADH. Pyruvate is taken into the mitochondrion as the base substrate for oxidative formation of ATP. Cytosolic NADH reacts with mitochondrial NAD+ (in essence, they switch places), with the net effect of pumping protons *out* of the mitochondrion. That is really the source of the cytosolic proton excess....mitochondrial respiration. In the mitochondria, 2 NADH + 2 H+ + O2 --> 2 NAD+ + 2 H2O. The cytosolic proton excess, however, comes at the expense of cytosolic NAD+, so acidosis may be a sign of NAD+ deficiency. There are many ways of looking at the same animal.
To summarize, there is always an ongoing balancing act between glycolysis (cytosolic) and oxidative respiration (mitochondrial). Whenever the mitochondria fall behind demand for ATP, the pyruvate production is imbalanced, and compensatory lactate is formed. However, lactate formation regenerates NAD+, and mops up protons, at the expense of energy efficiency.
Now, where we seem to part ways is on what comes first. Mitochondrial dysfunction is a very real entity, and I'm sure that it applies to my poor body. The root of mitochondrial dysfunction/low functioning is oxidative destruction of the two-layer mitochondrial membrane that is responsible for maintaining the proton/NAD shuttle. I see the oxidative stress as the root, and acidosis as the outcome.
> My interest is regarding my own brain fog, because if I improve buffering and support my mitochondria, my symtoms dramatically improve.
What is it, explicitly, that you do to improve buffering capacity? And separately, what do you do to support your mitochondria?
> Found this abstract on creatine as well..
>One thing at a time, Ray. I must pace myself.
Lar
Posted by raybakes on November 12, 2004, at 14:11:16
In reply to Re: dopamine oxidation » raybakes, posted by Larry Hoover on November 11, 2004, at 10:56:35
> OK, you bum, you made me get out my textbooks.Sorry Lar :(
I see the oxidative stress as the root, and acidosis as the outcome.I can go with that!
> What is it, explicitly, that you do to improve buffering capacity? And separately, what do you do to support your mitochondria?
Carnosine (good for detoxing aldehydes from mitochondrial lipid peroxidation), carnitine and creatine all work well for both.Do better with precursors - arginine and methyl factors for creatine - lysine and methyl factors for carnitine.
CoQ10 also needs methylation, and tyrosine, biopterin and cholesterol.
Also looking at ways to reduce superoxide and peroxynitrite as they uncouple a lot of mitochondrial enzymes.
The balance of arginine/NOS/biopterin/methylation seems important. Low biopterin or low arginine can switch NOS to produce superoxide instead of nitric oxide. Arginine without methyl factors can increase homocysteine.
I'm being cautious with NAC at the moment because although I want to raise glutathione, I get the feeling that cysteine dioxygenase (interleukin 1, 6 and TNF alpha related I think) doesn't clear the excess of cysteine properly for me - my lungs burned when I last took NAC. Do badly with sulfites (triggers superoxide production from NADPH), taking molybdenum worsens my symptoms, but MSM improves them dramatically
> One thing at a time, Ray. I must pace myself.
Sorry, hope that's not too much - I think I like forests more than trees!Ray
Go forward in thread:
Psycho-Babble Alternative | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.