58 replies to this topic

[Lufega]

I read discussion on inhibiting this system to allow for better absorption of supplements like curcumin and resveratrol perhaps, but I'm interested in doing the opposite.

Ideas ?

[leha]

Resveratrol actually inhibits CYP450, as do all macrolide antibiotics, so one thing you can do is to avoid those. Unfortunately, macrolides are fed to conventionally-raised food animals, so avoiding them means avoiding non-organic meats and dairy, as well as farmed fish.

I'm very curious as to why you are looking to upregulate CYP450, because I am also interested in possibly doing this, if it turns out that a problem I had with macrolides is related to their inhibitory action on CYP450. So far I have not been able to find a ton of research on the subject.

[Matt]

Broccoli =)

Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets
http://carcin.oxford.../21/6/1157.full

http://carcin.oxford.../4/793.full.pdf

Edited by Matt, 17 September 2010 - 03:48 AM.

[niner]

Resveratrol actually inhibits CYP450, as do all macrolide antibiotics, so one thing you can do is to avoid those. Unfortunately, macrolides are fed to conventionally-raised food animals, so avoiding them means avoiding non-organic meats and dairy, as well as farmed fish.

I'm very curious as to why you are looking to upregulate CYP450, because I am also interested in possibly doing this, if it turns out that a problem I had with macrolides is related to their inhibitory action on CYP450. So far I have not been able to find a ton of research on the subject.

There are a LOT of cytochromes P450. It's a whole family of enzymes, and they have very different substrate specificities. Some macrolides can inhibit one or two of them, but there are scores of others. Where you run into trouble with P450 inhibition is when a drug that you're taking is mostly or entirely metabolized by one of the P450s, and that's the one you inhibit with another drug. Then you will see your levels of the now-unmetabolized drug increase, possibly dangerously.

I'm opposed to feeding antibiotics to farm animals, but not because of the effects of any residual antibiotic in the resulting food. It would be nowhere near the dose needed to inhibit a p450.

I don't know of any way to upregulate ALL p450s, but I doubt Lufega really wants to do that. There are plenty of inducers of specific P450s, though many are drugs that you probably wouldn't want to take. The basic principle if you want to induce a metabolic enzyme is to give it a lot of its substrate(s). There are even some foods that will induce a couple of them.

[Lufega]

Resveratrol actually inhibits CYP450, as do all macrolide antibiotics, so one thing you can do is to avoid those. Unfortunately, macrolides are fed to conventionally-raised food animals, so avoiding them means avoiding non-organic meats and dairy, as well as farmed fish.

I'm very curious as to why you are looking to upregulate CYP450, because I am also interested in possibly doing this, if it turns out that a problem I had with macrolides is related to their inhibitory action on CYP450. So far I have not been able to find a ton of research on the subject.

I came across some research that implies that Essential tremor is caused by a metabolic problem in the Cyt P450 system. Basically, a substance called harmane (found in meats) is not converted to the less harmful harmine and it accumulates in the body and brain causing neurotoxicity and cerebellar degeneration (leading to essential tremor).

Niner got the basic idea of what I want to do but I can't figure out the biochemical pathway for this conversion. I can't even find the enzyme that converts harmane to harmine. If I could, I would be able to look up the substrates and possibly supplement them.

With this logic, I figure, a lot of the supplements inhibit the P-450 system, and in theory, could be making this problem worse for me. This harmane hypothesis is also implicated in Parkinson's disease, btw. I'm surprised we haven't heard more of this.

See my post on this subject here: http://www.imminst.o...sential-tremor/

Matt, thanks for the info. I just found out that sulforaphane is helpful in COPD so broccoli might just save the day here

[leha]

There are a LOT of cytochromes P450. It's a whole family of enzymes, and they have very different substrate specificities. Some macrolides can inhibit one or two of them, but there are scores of others. Where you run into trouble with P450 inhibition is when a drug that you're taking is mostly or entirely metabolized by one of the P450s, and that's the one you inhibit with another drug. Then you will see your levels of the now-unmetabolized drug increase, possibly dangerously.

I'm opposed to feeding antibiotics to farm animals, but not because of the effects of any residual antibiotic in the resulting food. It would be nowhere near the dose needed to inhibit a p450.

I don't know of any way to upregulate ALL p450s, but I doubt Lufega really wants to do that. There are plenty of inducers of specific P450s, though many are drugs that you probably wouldn't want to take. The basic principle if you want to induce a metabolic enzyme is to give it a lot of its substrate(s). There are even some foods that will induce a couple of them.

Thank you, niner; yes, the multitude of CYP450s was what made it so hard for me to track down any info, and I do agree that it's not likely that any known function of a CYP450 could be at the heart of a reaction to macrolides that occurs even when they are present in only trace amounts, BUT... this reaction is T-cell mediated, and involves some kind of cytokine signaling cascade, and does indeed occur after ingestion of incredibly small amounts of Tylosin in meats or dairy (or farmed fish). So... my reason to pursue it was that there might still be things we don't know about the workings of some CYP450s, AND when I recently tried a resveratrol supplement, I had this same reaction. It *might* have been something else I was exposed to; and it probably was. Nonetheless, when you are doing all your own research on an issue (Acute Febrile Neutrophilic Dermatosis) that medical science largely ignores, and in any case, is grossly misinformed about, it seems prudent to err on the side of caution. Plus, I was just surprised to see anyone else even interested in CYP450s here.

Lufega, your situation is a good example of what I'm talking about: people are still discovering what CYP450s might do or fail to do, and what kinds of messes we can get into when they aren't working right. I hope broccoli works for you--it's certainly a tasty option!

[niner]

I came across some research that implies that Essential tremor is caused by a metabolic problem in the Cyt P450 system. Basically, a substance called harmane (found in meats) is not converted to the less harmful harmine and it accumulates in the body and brain causing neurotoxicity and cerebellar degeneration (leading to essential tremor).

Niner got the basic idea of what I want to do but I can't figure out the biochemical pathway for this conversion. I can't even find the enzyme that converts harmane to harmine. If I could, I would be able to look up the substrates and possibly supplement them.

To be honest, I think this is a longshot. Although harmane can cause the same symptoms you see, that doesn't mean it's causal. But, FWIW... Harmane is metabolized primarily by P450 1A1 and 1A2. As it happens, broccoli and DIM found in cruciferous vergetables like brussels sprouts induce 1A2. In the broccoli paper, the subjects ate 500g/day, so I hope you like it. Apparently you'll also want to avoid apiaceous vegetables such as dill weed, celery, parsley, parsnips and carrots.

Quercetin is reported to induce 1A1. None of these inductions are necessarily guaranteed to be long lasting.

It might make more sense to just cut back on meat and (as if it weren't contra-indicated enough) tobacco, as well as any other sources of harmane you come across.

I did happen to run across a paper saying that harmane induces 1A1. That's kind of a good thing if you think about it; if you do have an excess of harmane in your diet, your body should respond appropriately.

[niner]

Thank you, niner; yes, the multitude of CYP450s was what made it so hard for me to track down any info, and I do agree that it's not likely that any known function of a CYP450 could be at the heart of a reaction to macrolides that occurs even when they are present in only trace amounts, BUT... this reaction is T-cell mediated, and involves some kind of cytokine signaling cascade, and does indeed occur after ingestion of incredibly small amounts of Tylosin in meats or dairy (or farmed fish). So... my reason to pursue it was that there might still be things we don't know about the workings of some CYP450s, AND when I recently tried a resveratrol supplement, I had this same reaction. It *might* have been something else I was exposed to; and it probably was. Nonetheless, when you are doing all your own research on an issue (Acute Febrile Neutrophilic Dermatosis) that medical science largely ignores, and in any case, is grossly misinformed about, it seems prudent to err on the side of caution. Plus, I was just surprised to see anyone else even interested in CYP450s here.

We love CYPs! So, it's more of an allergic reaction? That could be. The Tylosin level in meat is in the part per billion level, so you'd have to be awfully sensitive, but Tylosin ELISA kits exist, so it's not like it can't be immunogenic. Have you ever had a reaction (presumably really severe) to a therapeutic dose of a macrolide?

[e Volution]

As it happens, broccoli and DIM found in cruciferous vergetables like brussels sprouts induce 1A2. In the broccoli paper, the subjects ate 500g/day, so I hope you like it. Apparently you'll also want to avoid apiaceous vegetables such as dill weed, celery, parsley, parsnips and carrots.

Not being familiar with any of the underlying biochemistry, this sort of stuff scares me... Do you think the case is strong enough for potentially cycling vegetable intake so that there are intermittent periods of non-consumption for certain foods or food families?

[niner]

As it happens, broccoli and DIM found in cruciferous vergetables like brussels sprouts induce 1A2. In the broccoli paper, the subjects ate 500g/day, so I hope you like it. Apparently you'll also want to avoid apiaceous vegetables such as dill weed, celery, parsley, parsnips and carrots.

Not being familiar with any of the underlying biochemistry, this sort of stuff scares me... Do you think the case is strong enough for potentially cycling vegetable intake so that there are intermittent periods of non-consumption for certain foods or food families?

Well, you might not want to eat a daily gigadose of any particular food, but all this stuff is limited to 1A2, and these food classes have opposite effects. Then there's grapefruit (and other fruits) that affect 3A4. It's a good general rule to eat a varied diet. I wouldn't worry about cycling, just don't get stuck on one particular food.

[KimberCT]

I have essential tremor and have emailed Dr. Louis a couple times on this subject.  He mentioned that he would be exploring the harmane metabolism hypothesis soon.

Per my 23andme test, I'm a CYP1A2 fast metabolizer and CYP2D6 average metabolizer.  I've tried increasing my enzyme activity against the beta-carbolines by eating alot of broccoli sprouts, brussel sprouts, etc. and seasoning my meat with herbs like rosemary (which prevent harmane from forming).  After a few months, I don't really notice much of a difference.  I have my good days and bad days, but overall my tremor is still fairly mild (early onset, slow progression).

One thing I've recently considered is, the harmala alkaloids should upregulate the CYP P450 enzymes on their own.  Perhaps the problem isn't inherently low enzyme activity, but instead a failure of them to upregulate in the presence of the toxic beta-carbolines.  I've now just started looking at the aryl hydrocarbon receptor and how it interacts with substances that should increase enzyme activity.

FWIW, I believe this is the order of potency for metabolism of harmane:  major CYP2D6, CYP1A2, CYP1A1 - minor CYP2C19, CYP2C9, CYP2E1.  That's from memory and there were contradictory studies, so you can use those as a lead....

edit: Please PM me if you come across any interesting info or theories, I'll do the same.  It looks like we've been researching the same thing.

Edited by KimberCT, 17 September 2010 - 12:31 PM.

[bran319]

Anything that activates PXR will induc CYP enzymes and upregulate Phase I and II detoxification pathways. Interestingly this is a bioenergetically costly process and individuals with high levels of detoxification enzymes are correlated with longer lives and better health. The VDR, CAR have also been shown to upregulate certain enzymes but not on as broad a level as PXR.

Hyperforin, one of the main actives in St. John's Wort is a strong inducer of PXR. I believe Ginkgo also binds to it. D-alpha-tocopherol and Menaquinone-7 also bind to PXR. There are many others. A google search will be fruitful.

[niner]

Anything that activates PXR will induc CYP enzymes and upregulate Phase I and II detoxification pathways. Interestingly this is a bioenergetically costly process and individuals with high levels of detoxification enzymes are correlated with longer lives and better health. The VDR, CAR have also been shown to upregulate certain enzymes but not on as broad a level as PXR.

Hyperforin, one of the main actives in St. John's Wort is a strong inducer of PXR. I believe Ginkgo also binds to it. D-alpha-tocopherol and Menaquinone-7 also bind to PXR. There are many others. A google search will be fruitful.

I think PXR only raises 3A4 among the phase 1 enzymes, but also a handful of phase 2. Probably won't help for harmane.

[bran319]

Anything that activates PXR will induc CYP enzymes and upregulate Phase I and II detoxification pathways. Interestingly this is a bioenergetically costly process and individuals with high levels of detoxification enzymes are correlated with longer lives and better health. The VDR, CAR have also been shown to upregulate certain enzymes but not on as broad a level as PXR.

Hyperforin, one of the main actives in St. John's Wort is a strong inducer of PXR. I believe Ginkgo also binds to it. D-alpha-tocopherol and Menaquinone-7 also bind to PXR. There are many others. A google search will be fruitful.

I think PXR only raises 3A4 among the phase 1 enzymes, but also a handful of phase 2. Probably won't help for harmane.

Sorry, I don't know anything about harmane. I was responding to the OP. Is it a substrate for P-glycoprotein transport? PXR strongly affects P-glycoprotein.

Edited by bran319, 17 September 2010 - 02:24 PM.

[leha]

We love CYPs! So, it's more of an allergic reaction? That could be. The Tylosin level in meat is in the part per billion level, so you'd have to be awfully sensitive, but Tylosin ELISA kits exist, so it's not like it can't be immunogenic. Have you ever had a reaction (presumably really severe) to a therapeutic dose of a macrolide?

Well, technically, not allergic: allergies are mast cell mediated, and this is T cell mediated. That's why even a very small amount of the offending substance can set off a cascade resulting in neutrophilic infiltration of multiple organs, and for some reason, especially the skin. It's very similar to a severe drug reaction, but the underlying pathways differ from classic drug reactions. Both my GP and my immunologist have said that there was no test for macrolide sensitivity, but the evidence is overwhelming anyway, so I don't really need a test. I've been dealing with this for many, many years.

And yes, the first major reaction that tipped me off to what was going on was after taking a course of Azithromycin, another macrolide. Apparently for me they are all (or many of them, anyway) cross-reactive. The Azithromycin nearly killed me. It caused multiple classic Sweet's lesions all over my upper body, plus an inflamed spleen, erythema nodosum all over my legs and feet, and a sudden drop in blood pressure that required emergency intervention to keep me alive (I think it got to something like 70/30 before I passed out). I was sick for months after that, and had to take 60 mg prednisone for about 7 months before I finally weened myself off of it, though facing protests from both my GP and dermatologist. By that time, though, I had figured out about the trace amounts of tylosin in meats and dairy, and had eliminated those foods from my diet.

After that, I went through a period of mostly remission, with notable exceptions, always after eating at some restaurant, and finally figured out that most servers who say "there's no butter in it," or "the fish is wild," don't actually know for sure, and are often wrong. So I had to tighten my rules about what I could eat while in public, and now I'm chill.

Except... Recently I started two new supplements: resveratrol and l-arginine. Because of the CYP450 connection, I suspected the resveratrol when I first broke out, but it could also have been the l-arginine, which it turns out is not vegetarian.

The really interesting thing is that taking NAC seems to have a positive effect in resolving the rash, so lately I've been reviewing research on the relationship between the immune system and glutathione. I'm hoping most of all that I can help some of my fellow Sweet's Syndrome sufferers who have not been so lucky as me to discover what they were reacting to, and who have chronic, and very often constant bouts of painful lesions and organ problems. Medical science has all but left this small group of people for dead, unfortunately. There's been scant research funding devoted to SS, and doctors have repeatedly dropped fellow sufferers rather than deal with not knowing how to help them. It's pretty sad. I know one gal who is so sick she can't even log into the SS forum anymore to talk with us--and she was a very active member; in fact, she started the forum.

Well, hey, that's probably more than you wanted to know, but there it is, the whole reason we love CYPs!

[leha]

....
edit: Please PM me if you come across any interesting info or theories, I'll do the same.  It looks like we've been researching the same thing.

Whatever the two of you turn up, I think it's really cool that you've found each other here and that you both are researching and looking for answers.

[Lufega]

One thing I've recently considered is, the harmala alkaloids should upregulate the CYP P450 enzymes on their own. Perhaps the problem isn't inherently low enzyme activity, but instead a failure of them to upregulate in the presence of the toxic beta-carbolines. I've now just started looking at the aryl hydrocarbon receptor and how it interacts with substances that should increase enzyme activity.

I've hit a dead end with this since there is no more research that I find. I guess we have to wait until they figure this one out. There is the interesting paper about the mediterranean diet decreasing ET, but you said dietary intervention didn't work for you. Hmmm...

For starters, there has to be a way to test harmane levels to see with we are affected with a higher harmane/harmine ration but again, I came at a dead end. The easiest intervention to try out is what niner suggests..give up meat, coffe, wine and other foods high in beta-carboline for a while. See if that has any effect.

Edited by Lufega, 17 September 2010 - 07:52 PM.

[niner]

leha, thanks for filling us in. I'm glad you did because ImmInst has a pretty impressive collection of expertise, and you might find something that didn't turn up at the SS site. I think you can rule out the P450 connection on the basis of the tiny amount of macrolide that's able to trigger a reaction. The macrolides are generally inhibitory toward the 3A class of CYPs, though azithromycin, which nearly killed you, is not particularly a 3A inhibitor. Resveratrol inhibits (and not all that potently) 3A4 and has some minor activity in other classes. But every drug in the book is a CYP inhibitor to some degree. It's not really a defining characteristic of a molecule; "they all do it" is not that far from the truth. Importantly, CYP inhibition requires a significant amount of compound- parts per billion just won't do it. On the other hand, an immunological reaction at ppb levels is entirely possible, and sounds like exactly what's happening. Of the two supplements you were considering, Arginine is far and away a better candidate, as it could easily be contaminated with macrolide if it were made from animal protein hydrolysate. (I have no idea if that's the way they make it, but I can't for the life of me imagine how a macrolide could get into resveratrol.) You could do a test- try taking one of them and see what happens. Personally, I'd start with the resveratrol and if I didn't get sick, blame it on the arg. If you are a dedicated scientist, I suppose you'd have to sacrifice yourself to the pursuit of knowledge and try the Arg next. (but don't..) Sometimes I get sloppy about this, and this is a good reminder that I should only add one compound to my regimen at a time. (That can be really hard sometimes.)

You know, one thing comes to mind that might be helpful. You might be able to get a Tylosin ELISA kit so you could check supplements and food. Sometimes those are cheap, convenient and easy, sometimes not... It might help with some of these mysteries, if it's not crazy expensive.

[leha]

Thank you so much, niner. I did some looking around on the Internet and found a major distributor of the test kit selling them for around $400, so it might be awhile before I can pick that up.

I agree that it was much more likely the arginine was at fault. Unfortunately, it's made me start to worry about the gelatin in gelcaps! I guess if none of my other supps are giving me a hard time, that's probably okay, but it's truly amazing how little macrolide it takes to initiate lesions. And because of that, I'm somewhat reticent to perform tests on myself. SS lesions are incredibly painful!

There are a couple of factors I also have to consider when speculating about macrolides in foods: one big one is that I read somewhere that some dairies use as many as 20 different types of antibiotics in their feeds, vet medicine, etc., and I really have no way of knowing if it's *only* tylosin and azithromycin that set off my SS. I only know that tylosin is perhaps the most common macrolide in animal feed, that eliminating conventionally-raised animal foods from my diet was what finally stopped the ongoing lesions from appearing, and that azithromycin definitely nearly did me in. For all I know, I react to *all* macrolides, or some larger subset.

(I have some other clues from my history, BTW, that support that I've had this reaction for longer than just since the azithromycin dose--but I didn't know at the time what was causing the symptoms. For years I thought I was allergic to dairy products, but now that I know that it was the antibiotics in the dairy, I can eat organic dairy products with no problems.)

Again, thanks for your insights and for your concern.

Leha

[Lufega]

Harmane is metabolized primarily by P450 1A1 and 1A2.

Modulation of cytochrome P450 enzymes by organosulfur compounds from garlic.
Davenport DM, Wargovich MJ.

Department of Pathology and Microbiology, University of South Carolina, School of Medicine and South Carolina Cancer Center, Columbia, SC 29208, USA. matthew2@niehs.nih.gov


Abstract
Organosulfur compounds (OSCs) derived from garlic have been studied for the ability to inhibit experimental cancer in various animal models, primarily through modification of carcinogen detoxification enzymes, such as cytochrome P450 (CYP) enzymes. OSCs vary in structural and physical properties, and a detailed analysis of these properties has not been performed with respect to their ability of inhibit chemically-induced colon cancer development. Gastric intubation of rats with a single dose of 200 mg/kg diallyl sulfide (DAS), diallyl disulfide (DADS), and allyl methyl sulfide (AMS) decreased hepatic CYP2E1 protein by 45%, 25% and 47%, respectively, and this inhibition was sustained after 1, 4 and 8 weeks of treatment by these compounds. Dipropyl sulfide (DPS), dipropyl disulfide (DPDS), propyl methyl sulfide (PMS) and S-allylcysteine (SAC) did not inhibit hepatic CYP2E1 protein expression, nor did any of the OSCs affect CYP2E1 mRNA levels.


A single dose of 200 mg/kg DAS and AMS increased hepatic CYP1A2 protein (but not mRNA) by 282% and 70%, and DAS increased CYP1A1 protein levels by 684%. Daily treatment for 1, 4 and 8 weeks with 200 mg/kg DAS and AMS resulted in time-dependent increases in hepatic CYP1A1 and CYP1A2 protein levels to a maximum of 600% and 50% for DAS, and 1600% and 240% for AMS after 8 weeks. Dosing with 200 mg/kg of each of the OSCs used in this study increased hepatic CYP3A2 protein levels at all time points. Dosing for 8 weeks with 200 mg/kg DAS, but not AMS or lower doses of DAS, induced bile duct obstruction and focal areas of necrosis. These results indicate that OSCs present in garlic, including DAS and AMS, may be beneficial in inhibiting chemically-induced colon cancer, but that longer dosing with higher concentrations of DAS may elicit minor hepatic toxicity.

[Lufega]

Looks like the best source of DAS is garlic oil.

[Lufega]

Essential Tremor: One of the Most Common Neurodegenerative Diseases?
Full study:
http://content.karge...&file=000323572

CNS Neurol Disord Drug Targets. 2011 Mar;10(2):184-91.

Flavones from root of scutellaria baicalensis georgi: drugs of the future in neurodegeneration?
Gasiorowski K, Lamer-Zarawska E, Leszek J, Parvathaneni K, Yendluri BB, Blach-Olszewska Z, Aliev G.

School of Health Science and Healthcare Administration, University of Atlanta, 6685 Peachtree Industrial Blvd, Atlanta, GA 30360, USA. aliev03@gmail.com.

Abstract
Flavonoids are natural, plant-derived compounds which exert diverse biological activities, also valuable neuroprotective actions within the brain and currently are intensively studied as agents able to modulate neuronal function and to prevent age-related neurodegeneration. Among them, flavones isolated from Scutellaria baicalensis root exhibit strong neuroprotective effects on the brain and are not toxic in the broad range of tested doses. Their neuroprotective potential has been shown in both oxidative stress-induced and amyloid-beta and alpha-synuclein-induced neuronal death models. Baicalein, the main flavone present in Scutellaria baicalensis root, strongly inhibited aggregation of neuronal amyloidogenic proteins in vitro and induces dissolution of amyloid deposits. It exerts strong antioxidative and anti-inflammatory activities and also exhibits anti-convulsive, anxiolytic, and mild sedative actions. Importantly, baicalein, and also another flavone: oroxylin A, markedly enhanced cognitive and mnestic functions in animal models of aging brains and neurodegeneration. In the preliminary study, wogonin, another flavone from Scutellaria baicalensis root, has been shown to stimulate brain tissue regeneration, inducing differentiation of neuronal precursor cells. This concise review provides the main examples of neuroprotective activities of the flavones and reveals their potential in prevention and therapyof neurodegenerative diseases.

PMID: 21222632 [PubMed - in process]

Edited by Lufega, 14 February 2011 - 06:00 PM.

[leha]

Mmm... Broccoli with garlic!

[Lufega]

Polyunsaturated fatty acids are potent neuroprotectors.
Lauritzen I, Blondeau N, Heurteaux C, Widmann C, Romey G, Lazdunski M.

Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UPR 411, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.


Abstract
Results reported in this work suggest a potential therapeutic value of polyunsaturated fatty acids for cerebral pathologies as previously proposed by others for cardiac diseases. We show that the polyunsaturated fatty acid linolenic acid prevents neuronal death in an animal model of transient global ischemia even when administered after the insult. Linolenic acid also protects animals treated with kainate against seizures and hippocampal lesions. The same effects have been observed in an in vitro model of seizure-like activity using glutamatergic neurons and they have been shown to be associated with blockade of glutamatergic transmission by low concentrations of distinct polyunsaturated fatty acids. Our data suggest that the opening of background K(+) channels, like TREK-1 and TRAAK, which are activated by arachidonic acid and other polyunsaturated fatty acids such as docosahexaenoic acid and linolenic acid, is a significant factor in this neuroprotective effect. These channels are abundant in the brain where they are located both pre- and post-synaptically, and are insensitive to saturated fatty acids, which offer no neuroprotection.

Full study: http://www.ncbi.nlm..../pdf/cdd185.pdf

[KimberCT]

Lufega, have you tried high dose riboflavin supplementation?

It's problamatic because you can only absorb about 25mg at a time, so you have to dose frequently, but it seems to upregulate all the flavin dependent enzymes. I've been taking 100mg 6x per day for a couple weeks now and have seen some improvement in tremor and general mental health. I'd really like to find a flavin pro-drug that's better absorbed...

[Lufega]

Thanks KimberCT. Is this something you came up with or do you have any studies that show how it can be helpful ? I was researching another approach for treating ET, I'll post about it a little later. It seems that PD and ET have many parallels.

[KimberCT]

I just had this study as a lead...

http://www.tremoract...dfs/LICH_B2.pdf

...and then did some general research on the pharmacodynamics of riboflavin / flavin.

[Lufega]

it seems to upregulate all the flavin dependent enzymes.

Thanks for this info. I was unware of that site also. I'll read everything on there! How does upregulating flavin dep. enzymes help essential tremor ? What's the mechanism at work here ?

[KimberCT]

it seems to upregulate all the flavin dependent enzymes.

Thanks for this info. I was unware of that site also. I'll read everything on there! How does upregulating flavin dep. enzymes help essential tremor ? What's the mechanism at work here ?

Flavin dependent enzymes include, among others, some of the cytochrome P450 enzymes. If I recall correctly, however, CYP1A1 and 1A2 are not flavin containing enzymes. If harmane is the culprit in essential tremor and flavin supplementation works, it may be enhancing harmane metabolism through secondary pathways that do use flavin containing enzymes. Again, if I recall correctly, CYP2D6 and CYP2C19 are flavin containing P450 enzymes that have some affinity for harmane.

[Lufega]

Meat consumption is linked to ET because of the high harmane quantities. This may also apply to Parkinson's. High dose riboflavin supplementation improved some motor functions in some patients with PD. So again, the parallels are interesting. Is also worth mentioning the genetic relationship in this. My grandfather had ET most of his life. Now he has full blown PD. My father also has ET and is starting to show signs of PD; shakiness and slowness of movement, etc.

Braz J Med Biol Res. 2003 Oct;36(10):1409-17. Epub 2003 Sep 16.

High doses of riboflavin and the elimination of dietary red meat promote the recovery of some motor functions in Parkinson's disease patients.
Coimbra CG, Junqueira VB.

Setor de Neurologia, Hospital do Servidor Público Municipal de São Paulo, São Paulo, SP, Brasil. coimbracg.nexp@epm.br

Abstract
Abnormal riboflavin status in the absence of a dietary deficiency was detected in 31 consecutive outpatients with Parkinson's disease (PD), while the classical determinants of homocysteine levels (B6, folic acid, and B12) were usually within normal limits. In contrast, only 3 of 10 consecutive outpatients with dementia without previous stroke had abnormal riboflavin status. The data for 12 patients who did not complete 6 months of therapy or did not comply with the proposed treatment paradigm were excluded from analysis. Nineteen PD patients (8 males and 11 females, mean age +/- SD = 66.2+/-8.6 years; 3, 3, 2, 5, and 6 patients in Hoehn and Yahr stages I to V) received riboflavin orally (30 mg every 8 h) plus their usual symptomatic medications and all red meat was eliminated from their diet. After 1 month the riboflavin status of the patients was normalized from 106.4+/-34.9 to 179.2+/-23 ng/ml (N = 9). Motor capacity was measured by a modification of the scoring system of Hoehn and Yahr, which reports motor capacity as percent. All 19 patients who completed 6 months of treatment showed improved motor capacity during the first three months and most reached a plateau while 5/19 continued to improve in the 3- to 6-month interval. Their average motor capacity increased from 44 to 71% after 6 months, increasing significantly every month compared with their own pretreatment status (P < 0.001, Wilcoxon signed rank test). Discontinuation of riboflavin for several days did not impair motor capacity and yellowish urine was the only side effect observed. The data show that the proposed treatment improves the clinical condition of PD patients. Riboflavin-sensitive mechanisms involved in PD may include glutathione depletion, cumulative mitochondrial DNA mutations, disturbed mitochondrial protein complexes, and abnormal iron metabolism. More studies are required to identify the mechanisms involved.

PMID: 14502375 [PubMed - indexed for MEDLINE]

Full Study available here: http://www.scielo.br...v36n10/5318.pdf

Some excerpts:

In spite of an adequate dietary intake of riboflavin (FAD, vitamin B2), 10-15% of the inhabitants of London and of Florence present low activities of two riboflavin-dependent enzymes - erythrocyte glutathione reductase (EGR) and pyridoxin(pyridoxamine)-phosphate oxidase (5). The activity of both enzymes was corrected by adding their respective co-factors (FAD or FMN) to a test tube assay or by administering high doses of riboflavin (24-30 mg per day for 5-8 weeks) to the affected individuals (6).

Low EGR activity may explain glutathione depletion with impaired antioxidant defense, the earliest neurochemical abnormality in Parkinson's disease (PD), already observed
in the substantia nigra before the disorder becomes clinically evident (7).

Moreover, the reduced bioavailability of FMN and/or FAD may also explain the impaired oxidative metabolism of PD patients (8-10).

About 10 to 15 days after the beginning of high-dose riboflavin treatment, PD patients often reported better (progressively less interrupted) sleep at night, improved reasoning, higher motivation, and reduced depression.

The initial riboflavin status was low in all 31 consecutively evaluated PD individuals, and significantly lower in PD patients compared with those with another neurodegenerative disease also associated with hyperhomocystinemia (DwoSt), suggesting that abnormal riboflavin status may be a specific feature of PD rather than a minor metabolic contributor to the degeneration of nigral neurons. Taken together with the rapid and profound neurological improvement associated with normalization of riboflavin status, this observation suggests that altered riboflavin status may be a cause of neurodegeneration in PD.

However, the digestion of red meat releases hemin, a highly diffusible toxin that, when not properly inactivated, increases intracellular iron concentrations and enhances hydroxyl radical production (Fenton reaction). Most of the absorbed hemin is destroyed by the enzyme heme oxygenase (HO) in the digestive tract and liver (26). Because HO is oxidized during the catabolization of hemin to biliverdin, the HO molecules must be reduced through the coordinated activity of the flavoenzyme cytochrome P450 reductase for continued hemin inactivation (Figure 2) (27). Cytochrome P450 reductase is particularly sensitive to riboflavin deficiency because it requires both FMN and FAD as prosthetic groups (28). It is possible that individuals with decreased absorption of vitamin B2 may not completely inactivate high dietary levels of hemin, allowing this neurotoxic compound to reach the brain cells.

Flavin dependent enzymes include, among others, some of the cytochrome P450 enzymes. If I recall correctly, however, CYP1A1 and 1A2 are not flavin containing enzymes. If harmane is the culprit in essential tremor and flavin supplementation works, it may be enhancing harmane metabolism through secondary pathways that do use flavin containing enzymes. Again, if I recall correctly, CYP2D6 and CYP2C19 are flavin containing P450 enzymes that have some affinity for harmane.

In ET, it's harmane that is not metabolized and becomes neurotoxic. In PD, this appears to be hemin. Both are derived from meat consumption. So, your proposed mechanism for riboflavin's efficacy appears to be correct.

Edited by Lufega, 16 February 2011 - 06:20 PM.