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MONOAMINE OXIDASE (MAO) AND MONOAMINE OXIDASE INHIBITORS (MAOIs).
In the following study, persons with hyperthyroidism were found to have low levels of MAO and DAO (histaminase), both of which are copper-containing enzymes. This is excellent evidence that a copper deficiency is a key part of hyperthyroidism.
Circulating levels of T3, T4, gamma-amino-butyric acid, glutamate, 5-hydroxytryptamine, histamine, monoamine oxidase and histaminase were studied in 45 (25M, 20F) hyperthyroid patients and 46 (25M, 21F) normal healthy volunteers. Increased levels of blood 5-hydroxytryptamine, histamine and glutamic acid were observed along with elevated T3 and T4, whereas plasma gamma-aminobutyric acid, monoamine oxidase and histaminase activities were found to be low in both male and female patients. After three months of treatment, circulating levels of 5-hydroxytryptamine, histamine and glutamic acid decreased significantly along with normalization of thyroid hormones and with an increase in the concentrations of gamma-aminobutyric acid, monoamine oxidase and histaminase. There was a positive correlation between these amines and thyroid hormone levels. The findings thus suggest that alterations in the metabolism of biogenic amines may be related to an altered metabolism in thyrotoxicosis, and these parameters may prove to be useful markers for diagnosis and follow-up of these patients.
In the following study monoamine oxidase (type B) and diamine oxidase were found to be low in psoriasis patients while histamine was found to be high. Diamine oxidase is a copper-containing enzyme which breaks down histamine. Histamine is also responsible for asthma which is the reason antihistamines are recommended for asthma. Asthma is probably another disease of copper deficiency.
Monoamine- and diamine oxidase activities were measured by a sensitive photometric assay in 25 psoriasis vulgaris patients. Results were compared with plasma histamine values determined fluorimetrically. Increased plasma histamine levels were associated with significantly lowered diamine--and type B monoamine oxidase activities in platelet-rich plasma of the psoriasis patients. Our data suggest that cofactor levels and/or inhibiting factors are responsible for the observed monoamine- and diamine oxidase activities.
The roots and/or rhizomes of Glychyrrhiza uralensis, G. glabra and G. inflata, and commercial licorice specimens from various regions or countries were analyzed by high-performance liquid chromatography (HPLC), and classified into three types based on their phenolic constituents. i) Type A: The roots and rhizomes of G. uralensis, commercial licorice specimens from northwestern region of China (Seihoku-kanzo) and from northeastern region of China (Tohoku-kanzo) in Japanese markets, and also several licorice specimens from Chinese markets. They contain licopyranocoumarin (6), glycycoumarin (7) and/or licocoumarone (8), which were not found in G. glabra and G. inflata. ii) Type B: The root and rhizome of G. glabra, and the licorice specimens imported from the Soviet Union and Afghanistan. They contain glabridin (9) and glabrene (10), which were not found in the samples of the other two Glycyrrhiza species. A root sample of Glycyrrhiza species from Turkey also contains 9 and 10. iii) Type C: The root sample of G. inflata. They contain licochalcones A (11) and B (12), which were not found in the samples of the other two Glycyrrhiza species. Commercial licorice specimens obtained in Japan, which were imported from Sinkiang of China (Shinkyo-kanzo), and some licorice specimens obtained from Chinese markets, have also been found to contain 11 and 12. The phenolics 6-12, characteristic constituents of types A, B or C, were not found in a specimen of cortex-free licorice from a Japanese market (kawasari-kanzo). Extracts of some licorice specimens of types A and B, and all of the licorice specimens of type C inhibited 40-56% of the xanthine oxidase activity at the concentration of 30 micrograms/ml. Extracts of some licorice specimens of types A and B also showed inhibitory effects on monoamine oxidase (44-64% inhibition, at the concentration of 30 micrograms/ml), which were slightly weaker than that of harmane hydrochloride.
This study determines if one could distinguish foregut from midgut carcinoid tumors by quantitative measurement of the monoamine oxidase (MAO) and diamine oxidase (DAO) activities in homogenates of tumors. The MAO activity of 16 foregut carcinoid tumors (1850 +/- 342 pmol/mg/minute) was significantly higher than the MAO activity of 11 midgut carcinoid tumors (407 +/- 43 pmol/mg/minute, P less than 0.01) with no overlap between the groups. Although all ten of the midgut carcinoids had measurable DAO activity (720 +/- 190 pmol/mg/minute), with the exception of one duodenal carcinoid tumor (33 pmol/mg/minute) the nine foregut carcinoid tumors evaluated did not have detectable DAO activity. The MAO activity of all of the foregut carcinoids was higher than that of 6 islet cell tumors, 28 paragangliomas, and 12 medullary carcinomas of the thyroid. Quantitative MAO and DAO activity may be useful in distinguishing foregut carcinoid tumors from other related tumors.
Occasional patients with medullary carcinoma of the thyroid (Multiple Endocrine Neoplasia Type II [MEN II]) are reported to have excessive serotonin (5-HT) production from the MCT; almost all patients with metastatic MCT have elevations in plasma concentration of the amine oxidase, histaminase. The elevated 5-HT production is thought ot contribute to the troublesome diarrhea experienced by patients with MEN II. We compared the urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the principle metabolite of 5-HT, of 33 patients with MCT with the urinary excretion of 5-HIAA in 33 control subjects. Six of the 33 MCT patients (18%) had severe diarrhea. The 5-HIAA excretion of the MCT patients did not differ from that of normal subjects. We also compared the platelet monoamine oxidase (MAO) activity of 27 MCT patients and 27 control subjects. The platelet MAO activity of the two groups did not differ. The 5-HT content and MAO activity of 6 of the MCTs was similar to normal thyroid tissue. The MAO activity of two follicular adenomas of the thyroid was greater than the MAO activity of MCTs. In contrast to the uniform elevation of plasma histaminase in patients with MCT, the platelet MAO activity is not altered and the majority of MCTs do not produce excessive amounts of 5-HT.
MONOAMINE OXIDASE POST TO GROUP, Jan.14, 1999
When I learned about monoamine oxidase (MAO) I had a feeling that this could be a very big story for hypers and pheos. When I did a Medline search of MAO I found over 1300 scientific studies dealing with it. There is no doubt in my mind now that MAO deficiency is a major cause, and perhaps the biggest cause, of hyperT and pheo.
As I explained before, I am going to reorganize my posts on these studies and give a summary first. This way you can determine if this study is pertinent to you and the layout will conform more to the standard organization of reports on scientific studies.
There are many studies which show that monoamine oxidase (MAO) is a copper-containing enzyme which deactivates the catecholamines (norepinephrine, epinephrine, and dopamine) after their function has ended. There are some studies showing that MAO deficieny increases thyroid hormones. One study showed that a copper deficiency causes a deficiency of MAO. Another study stated that MAO contains iron. Several studies showed that long-term exposure of rats and humans to manganese (a copper and iron antagonist) causes MAO deficiency. Many of the symptoms seen in hyperT and pheo are appear directly attributable to MAO deficiency from copper deficiency. Stress initiates higher production of catecholamines which require more MAO for degradation, and thereby may cause decreased copper levels. These nutrients appear to be necessary for MAO production: copper, iron, riboflavin, histidine, and vitamin C.
The full story is more complex. First there are two isozymes of MAO: MAO-A and MAO-B. Also there are other similar enzymes that degrade hormones and neurotransmitters. (The terms degradation, deamination, and deactivation will be used interchangeably in this story.)
There is a diamine oxidase (DAO) which has two amines instead of the one amine in MAO. There is dopamine beta-hydroxylase (DBH). There is also semicarbizide-sensitive amine oxidase (SSAO) and others. I don't want to make it complicated but just want you to be aware that there is a whole family of oxidases which degrade hormones and neurotransmitters.
MAO is well studied and has been shown to contain topa quinone. Topa is 2,4,5-trihydoxyphenylalanine (built on the amino acid phenylalanine) and copper is essential for its production. MAO contains histidine, another amino acid. I will do another post on histidine in the future. Since histidine is an amino acid found in proteins, I don't think you need to supplement it, but it is available as a supplement if you wish to try it.
One study directly showed that a copper deficiency causes a deficiency of MAO. Another study indicated that MAO contains iron. Another study showed that copper and flavin (riboflavin) were necessary for MAO production and that the human heart has high MAO-B activity. This suggests to me that MAO deficiency could cause increased heartrate and therefore a copper and/or iron deficiency can cause increased heart rate. Another study showed that imbalances in body levels of copper and zinc can cause hypertension and that low MAO causes higher blood pressure.
The catecholamines, epinephrine (the other name is adrenalin), norepinephrine (noradrenalin), and dopamine, are the stress hormones which get your body ready for fight-or-flight emergencies. In normal humans (and other mammals), MAO-A and MAO-B deactivate these hormones so that the body can return to a calm state. When the animal is frightened by a primary or conditioned response stimulus, these hormones are squirted into circulation to increase heartrate, breathing rate, and blood pressure to ready the animal for fighting or running away. If the MAOs are lacking, then these hormones are not degraded and remain in circulation for a long time, causing the prolonged panic and anxiety attacks seen in hyperT and pheo.
Studies show that both MAO-A and MAO-B deaminate norepinephrine, with MAO-A deactivating about 2/3 of the norepi and MAO-B deactivating 1/3. Many people have depression and fatigue caused by insufficient amounts of the stimulating catecholamines (perhaps from insufficient tyrosine or phenylalanine in their diets, or other nutrient deficiencies). Doctors often prescribe monoamine oxidase inhibitors (MAOI) to increase the available amounts of the catecholamines. L-Deprenyl (Selegiline) is a drug which inhibits MAO-B, while Clorgyline inhibits MAO-A. Other MAO inhibitors are ifenprodil and beflaxatone. If you are taking any drugs, find out through the Physicians Desk Reference (PDR) whether those drugs are MAOIs.
Studies have shown that norepi increases during chronic MAO inhibition through the use of an MAOI. So the studies show clearly that norepi and the other catecholamines are decreased by MAO and increase when MAO is deficient.
Several studies on rats have been done to see the effects of MAOs on thyroid hormone. Methimazole (trade name Tapazole) has been shown to increase MAO activity (mainly MAO-A) and thereby increase TSH. Another study showed that MAO inhibitors increase T4, showing that low MAO causes increased thyroid hormone. Another study showed that an MAOI increased wheel running in normal (euthroid) rats more than hypothyroidic rats, indicating that MAOs affect the thyroid levels. Another study showed that rats treated with thyroxin (T4) had decreased levels of MAO, and those treated with carbimazole (methimazole) had increased levels of MAO.
Quite a few studies have been done on rats showing the effects of manganese on MAO. One study showed that prolonged exposure to low levels of manganese caused MAO to be decreased significantly. Another study showed that manganese given to rats at high levels showed significant reduction in both MAO-A and MAO-B. Another study showed that manganese in rat drinking water decreased dopamine beta-hydoxylase. A study showed manganese-exposed human workers in a ferro-alloy manufacturing plant had lower MAO-B activity. Since manganese is copper and iron antagonist, it appears that the effects of manganese on MAO are mediated by decreasing copper and iron levels.
Studies on manganese and thyroid function are less conclusive but suggestive. One study showed that manganese deficiency increases 5'-deiodinase activity (increased conversion of T4 to T3), while another study showed that excess manganese caused thyroid abnormalities (?). It appears that excess manganese can have significant effects on catecholamine levels (and possibly thyroid levels) by decreasing both MAOs significantly. I think all pheos and hypers need to determine if their manganese levels are high. Since many multiple vitamin/mineral supplements contain 5-10 mg of manganese, the use of these products in pheos and hypers with high body levels of manganese could be very detrimental. Supplementation with copper and iron in very important whether or not manganese levels are high.
One study was performed on the effects of stress on cardiovascular and cerebrovascular disorders (heart and brain circulation). The study showed that high levels of stress cause high levels of epinephrine. The epi is deactivated by MAO to form methylamine which is then converted by SSAO (semicarbizide-sensitive amine oxidase) to formaldehyde, hydrogen peroxide, and ammonia. These chemicals can cause extensive damage to the brain and heart. This appears to be what happens in pheo and untreated hyperT.
Another study showed that SSAO is active in many part of the eye. My speculation is that high levels of catecholamines or thyroid hormones in the eye may cause SSAO to produce excess formaldehyde or other breakdown products which may damage the eye. Since riboflavin is involved in MAO production and also helps prevent many eye problems, there may be some connection.
One study showed that in ulcerative colitis, which is an inflammation of the colon, there is a deficiency of diamine oxidase and MAO which decreases the ability of the bowel to produce the amino acid GABA which then leads to an inflammation of the mucosa. Since hypers (I don't know about pheos) have bowel problems (diarrhea etc.), then there may be some connection here.
Several studies have been done on whether B-12 deficiency affects MAO. One study showed no association. Another showed B-12 status is a controlling factor in platelet MAO activity (I don't know what this is.) Another study showed a negative association between MAO-B activity and B-12 levels. This indicates that when B-12 is administered, MAO-B activity decreases. I have speculated in the past that B-12 shots seem to increase hyperT symptoms. I think that when B-12 is taken without iron it causes the iron to be further depleted.
Literature on copper indicates that high copper levels can lead to schizophrenia by deactivating the catecholamines and serotonin. In other words high levels of copper can increase the MAOs and thereby cause deficiencies of catecholamines and serotonin. Do hypers and pheos have to worry about getting too much copper and becoming schizophrenic? I don't think so. First the copper would have to increase to the point where the MAOs would be high enough to eliminate all symptoms of their disease, and then as copper increased more you would get hypothyroid, and then more copper would lead to severe depression and fatigue. Finally very high levels of copper could lead to schizophrenia. More than likely these high levels of copper cannot be achieved without taking massive doses of copper (over 50 mg a day) and/or not taking the other minerals which work with copper (iron, sulfur, zinc, etc.) Hypers and pheos seem to be on the extreme other end of the spectrum of copper levels from the schizophrenics.
An interesting study showed that there is a Dutch family which has a genetic defect which causes a deficiency of MAO-A (which degrades serotonin and norepi). Norepi increases anger, while serotonin suppresses fear. The men in this family had double the normal levels of norepi and nine times the normal levels of serotonin. The high norepi made them get angry easily and the high serotonin almost completely eliminated any feelings of fear. The result: high aggression and violent behavior. They get angry and have no fear of the consequences of attacking those who make them angry.
People with high fear levels (phobias, anxiety, etc.) are usually deficient in serotonin. The amino acid tryptophan is converted into niacin which is converted into serotonin. Supplementation of tryptophan (you'll need a doctor's prescription) or niacin will increase serotonin production and lower fear levels. Prozac and other similar drugs increase serotonin by decreasing its degradation, enabling the users to live life with less fear. It's easy to do the same thing by increasing tryptophan in the diet or supplementing with more niacin (and safer too.)
In summary, we have known for a long time that copper decreases the symptoms of hyperthyroidism but had only one explanation for the possible action--increasing estrogen production, which suppresses thyroid activity. Now we have what is probably the most important reason why copper helps hypers (and hopefully pheos)--it is essential for production of MAOs which deactivate the catecholamines and the thyroid hormones. Low copper leads to low MAO which leads to hyperT and pheo. Also low levels of the other nutrients known to be involved in MAO production may play a role: iron, histidine, riboflavin, and vitamin C. It is quite likely that other nutrients are essential for MAO production.
Whether MAO can be taken directly to control hyperT and pheo is an interesting question for which I have no answer. If it were possible to obtain MAO, this would be a great experiment which could show us whether MAO deficiency is causing these diseases. I saw no study in which MAO was administered to any human or other animal, so perhaps it doesn't exist.
Because there seem to be many of these oxidases, the best solution seems to be to increase the nutrients needed to produce them. Since these nutrients seem to be the ones that we have been using, then it appears that if MAO deficiency is the cause of these diseases, then we are proceeding in the right direction.
The one new discovery from this in regards to what nutrients may be important in recovery from hyperT and pheo is histidine. Histidine is an amino acid that I suspected was involved a few weeks ago. I have been supplementing with it on and off for a few weeks now and haven't noticed any big effects. But it might have a big effect on anyone who is deficient in it or who has hyperT or pheo. I suspect that a high protein diet will supply an adequate amount of histidine and that the limiting nutrients for most hypers and pheos are copper, iron, and the B-complex vitamins.
I will continue studying the degradation of hormones and feel that right now this seems to be the most promising area of research for hyperT and pheo. I will also try to determine if some hypos have excess MAO and this is the cause of their condition. I suspect that most hypos are deficient in the nutrients needed to make thyroid hormone, some possibly from excess levels of competing nutrients or toxic metals.