Histamine’s broad role in our bodies makes it relevant to nearly every major system. As such, dysregulated histamine can impact nearly every major system. Be it from a downregulated HNMT gene, excess histamine consumption, or gut dysbiosis—resulting sometimes in histamine intolerance (HIT)— can wreak absolute havoc on a body.
Both dietary and genetic considerations dictate the dynamics of histamine in our bodies. Research shows those with certain genetic variations are more susceptible to histamine dysregulation. Further complexity arises from the influence of certain foods and supplements on histamine.
- Histamine plays a complex role in the human body
- Histamine intolerance (HIT) may result from many issues
- Several key genes help regulate histamine and may play an integral role in HIT
- Histamine genes may be blocked, inhibited, or even upregulated by certain medicines, supplements, and foods.
- Terms like “histamine liberators” are common among histamine diets but not defined in research.
Histamine Intolerance is thought to affect as much as 1% of the global population with the majority being middle-aged persons (21). Having a general idea of histamine’s role in the body can help one better understand conditions like histamine intolerance (HIT), mast cell activation syndrome (MCAS), and possible personal risk factors.
Modern science is quickly understanding the role our genes play in health, with a budding awareness specific to the influence of nutrition (22). Histamine is no exception here; genes coding for HNMT, DAO, and even MAO-B are all understood to affect histamine in our bodies, all of which can be influenced by dietary factors.
Understanding some basics of the interplay between these genes, our environment, and what we eat may help provide the understanding needed to better navigate histamine intolerance and other related conditions. At the very least, it is an interesting topic!
Histamine Regulating Genes
Histamine plays a complex role in the human body. As such, the body needs some complex systems in order to fully utilize it. Among these tools are a set of genes and enzymes that help metabolize histamine, recycle it, and get rid of excess metabolites. Below are some of the more notable of these compounds.
Histamine N-methyltransferase (HNMT)
HMNT is an enzyme that metabolizes histamine in tissue but not in the bloodstream (4). It’s associated largely with neuronal histamine metabolism and functions through methylation via s-adenosyl methionine (SAMe). Particularly illuminating to the nature of HNMT’s role in the body, research has shown it to influence the sleep-wake cycle and aggressive behavior (9).
HNMT activity is directly related to the activity of the methylation cycle where its activity is controlled by S-adenosyl methionine (SAMe) via methyl donation (31). Any genetic mutations affecting the methylation cycle may therefore result in affected HNMT activity. Research has shown several pharmaceutical drugs as inhibiting the activity of HNMT as well, to varying degrees (34).
For more information, I suggest reading this excellent article on methylation (and SNPs in general) by Dr. Suzy Cohen.
Diamine Oxidase (DAO)
DAO is the enzyme responsible for metabolizing histamine and several other polyamine compounds (5). Studies have shown that supplementation with DAO prior to meals can reduce symptoms associated with Histamine Intolerance (8). These include gastrointestinal, skin, and respiratory issues.
Several SNP mutations have been shown to play a significant role in the expression of DAO (30). This is very relevant to measured DAO activity but has not yet been directly connected with conditions such as Histamine Intolerance.
The AOC1 gene is responsible for producing DAO and mutations have been implicated in a range of histamine-related conditions such as histamine intolerance. Note: SNPs related to DAO may be referred to as DAO, AOC1 or ABP1.
Monoamine Oxidase (MAOB)
MAOB is responsible for metabolizing monoamines such as hist-amine and dop-amine. MAOB inhibitors are used to treat certain conditions such as Parkison’s Disease. Genetic mutations associated with the MAOB can affect levels of both dopamine and histamine (10). With this fucntion in mind, it is easy to understand how research has painted a clear connection between MAOB SNPs and negative emotional outcomes (27).
MAOB is responsible for the final stage of histamine clearance—converting N-methylhistamine to N-methyl-imidazole acetaldehyde. The accumulation of N-methylhistamine can block the upstream activity of HMNT leading to possible accumulation of histamine (28). In related science, overexpression of MAOB has been linked to age-related cognitive decline as seen in conditions such as Alzheimer’s Disease (29).
Aldehyde Dehydrogenase (ALDH)
ALDH helps reduce metabolites of histamine and putrescine after having been converted by DAO and HNMT (11). The versatile activity of this compound illustrates how certain other biogenic amines like putrescine can compete for metabolism with compounds like histamine. In other words, increased levels of putrescine could result in less histamine being metabolized.
The ALDH enzyme is also involved in the metabolism of alcohol in such ways that would also compete with the metabolism of histamine (12). Research, while thin on outcomes relevant to histamine levels, has shown significant relationships with other major health conditions like atrial fibrillation and breast cancer (25)(26)
Histidine decarboxylase (HDC)
HDC is the enzyme that converts the amino acid histidine into histamine. Histamine can not be created by any other known pathway in the body making the HDC gene the sole regulator of histamine synthesis from histidine (23). Similar in activity to mast cells, the HDC enzyme has shown to be responsible for increases in histamine in response to many types of antigens (6).
Curiously, research has shown that mast-cell knockout mice still produce histamine in significantly elevated amounts via the HBD gene in response to allergens. Research has also shown a significant relationship between SNP mutations in the HDC gene and the development of allergic rhinitis (24).
Below is a table containing many compounds having demonstrated DAO-inhibiting activity. These compounds, some of more relevancy to modern life than others, should be realized as the decades-old data they are: 1985 to be exact. Noteworthy inclusions are Ascorbic Acid, Dopamine, Thiamine, and Acebutolol (a first-gen antihistamine).
Note: the % inhibitions are listed from left to right in descending order of concentration (1 x 10-5 being the least concentrated)
|Concentration||1 x 10-5||1 x 10-4||1 x 10-3|
There are some noteworthy considerations here. First, Ascorbic Acid is often among the first compounds I see mentioned as a “natural antihistamine” and rightfully so. Research confirms that serum histamine levels have an inverse relationship with serum ascorbic acid levels (3)–more vitamin C equals less histamine.
These data show that “higher” levels of ascorbic acid might need better definition when addressing histamine. It seems levels that are too high may actually inhibit the DAO enzyme. This suggests more frequent dosing with lower amounts may prove more effective at managing histamine levels.
Also of interest, DAO requires another compound named flavin adenine dinucleotide (FAD) as a co-enzyme. which in turn requires riboflavin (vitamin B2) (20). Researchers have noted, through a complicated intercellular dance, that riboflavin can help boost DAO activity by increasing the level of FAD within cells!
Note: DAO is available as a supplement* but does not get absorbed. It can only help metabolize histamine that from foods and does not act to lower systemic histamine levels. The general recommendation is to take DAO supplements 10-15 before meals.
Diphenhydramine, a common first-gen H1 blocker (a.k.a. Benedryl) is an example of an HNMT blocker (15). This compound, along with many others, has shown significant blocking potential of the HNMT enzyme resulting in downregulated metabolism of histamine. This illustrates one way in which prolonged use of antihistamine drugs, even OTC variations, could result in poorer overall histamine metabolism. Below are several other HMNT blocking compounds:
- amodiaquine (anti-malarial)
- metoprine (anti-folate)
- tacrine (anticholinergic)
The Mast Cell Disease Society maintains several resources listing common medications that may trigger mast cell activation (and thus histamine release.) I suggest anyone concerned with negative histamine reactions read through their literature (it’s very user-friendly.)
Inhibition of the HDC enzyme would result in lower levels of histamine. This may be favorable results for those with histamine intolerance issues, allergies, or other concerns associated with high levels of histamine. Among the many compounds implicated in HDC inhibition are the following (16):
- Salicylic Acid
- Phthalic Acid
MAO inhibitors are popularized for treating health conditions such as depression, Parkinson’s Disease, PTSD, and a range of other conditions associated largely with neurotransmitters such as dopamine and serotonin.
Generally, MAO-inhibitors come in two flavors: MAO-A inhibitors and MAO-B inhibitors. Given MAO-B is the enzyme responsible for histamine metabolism, that’s what we’ll discuss here. Below are several natural compounds having demonstrated mild to strong MAO-B inhibition (17)
Kava kava has also been shown to be a potent inhibitor of MAO-B but does not exhibit the same inhibitory effect on MAO-A (18). For those with MAO-B genetic mutations, Kava may not be such a relaxing endeavor.
Conversely, riboflavin has shown some potential as an MAO-B boosting agent that may provide neuroprotective support (19).
High Histamine Foods & Histamine ‘Liberators’
It doesn’t take long to find low-histamine diet food lists online–there’s certainly no shortage. From the research I’ve seen, it is hard to make a case for many whole-foods that aren’t spoiled as being “high histamine.” Foods like sour kraut, sausage, cheeses, and aged beef are non-brainers. However, whole foods like vegetables and fruits aren’t as clear-cut of cases.
I’ve seen limited research describing the effects of different cooking methods on histamine (13) and I’ve seen research describing the histamine content of plant-based foods (14). There are some clear culprits like spinach, eggplant, and tomatoes. However, research suggests that other common mentions like peanuts, avocados, and lemons may not be high in histamine content.
In addition to high histamine foods, one might often also see the term histamine liberators. These are compounds that supposedly cause histamine release within the body. I have not seen any medical literature describing the nature of histamine “liberation” as it relates to foods, universally among those without food-based allergies.
Histamine is a very utilized compound throughout the human body. It plays a key role in digestion, cognition, respiration, and a number of other major biological functions. Simply put, the human body would be a very different design without histamine. As with most resources that are heavily utilized, the wide range of enzymes, cofactors, and genetics involved with histamine metabolism is immense, complex, and very interconnected.
Histamine intolerance is a very real condition that is still in the early stages of clinical understanding. Other similar conditions such as mast cell activation syndrome (MCAS) have many parallels in that histamine plays a pivotal role. High dietary histamine, consumption of compounds that compete for metabolism, and compounds that block the activity of key enzymes can all play a complex role in how our bodies handle histamine.
As a final thought, drawn deeply from personal experiences, I’d caution everyone to consider how unique each of us truly is. The compounds that work in helping one person address histamine issues may derail your health progress. For example, quercetin is among the most well-studied natural antihistamines in the world. For someone with a genetic mutation in their MAO-B gene, however, quercetin might just further downregulate it such that the negatives outweigh the positives.
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