Origin of Biogenic Amines
Biogenic amines, including histamine, are formed in food by the action of decarboxylase enzymes of micro-organisms from precursor amino acids. This is not the case for natural or physiological amines, which are formed during metabolic processes in plant and animal cells.
The precise establishment of the biogenesis of these amines in food is complex. This difficulty is due to the possibility of alternative biosynthetic routes, coupled with the combined involvement of different types of micro-organisms and their possible interactions.
Therefore, specific requirements are needed for histamine to be produced in food:
-
- Growth of micro-organisms with decarboxylase activity.
- Availability of amino acid precursors and necessary cofactors.
- That physico-chemical conditions are favorable for the decarboxylases’ synthesis and activity (pH, Aw, temperature, etc.).
Food Histamine Metabolism
All food, since the moment it enters the oral cavity, is composed of nutrients that require metabolization for subsequent absorption or excretion. The organs of the digestive system complete the digestion of food by obtaining the nutrients necessary for the body to function. This function is carried out, in part, by digestive enzymes released into the intestinal tract by the different sources of secretion (salivary, gastric, pancreatic, intestinal and biliary).
Histamine, a molecule that exists in all foods, whether of animal or vegetable origin, must also be metabolized in order to be eliminated in the urine without inconvenience. It should be noted that exogenous histamine has no functional role in the body and is therefore eliminated without benefiting from any properties.
There are two major routes of histamine metabolism in living organisms, involving the enzymes Histamine-N-Methyltransferase (HMT) and Diamine Oxidase (DAO).
Degradation by Histamine-N-methyltransferase (HMT or HNMT)
In this route, histamine undergoes ring cleavage by the enzyme HMT. Subsequently, a large part of the product, N-methylhistamine, is transformed from Monoamine Oxidase (MAO) into N-methylmydiazole acetaldehyde. Finally, the enzyme Aldehyde Dehydrogenase (ADH) transforms it into N-methylimidazole acetic acid.
HMT is the enzyme that degrades histamine in liver tissue, but it is also expressed in many other tissues (in smaller amounts). Many studies establish a weak correlation of HMT in histamine metabolism in the intestinal mucosa, as its activity is almost negligible compared to the activity of the enzyme DAO.
Histamine-N-methyltransferase is a cytosolic protein and therefore can only convert histamine in the intracellular space of cells. For this reason, its ability to metabolize histamine is less than that of the Diamine Oxidase pathway, which plays a role in the inactivation and elimination of extracellular histamine. This correlates with the fact that pathologies related to high histamine concentrations in the blood are associated with DAO Deficiency and not HMT.
Degradation by Diamine Oxidase (DAO)
In this pathway, histamine undergoes an oxidative deamination catalyzed by DAO. The products are imidazole acetic acid and its riboside. The two metabolites of the histamine pathway, imidazole acetic acid and N-methylimidazole acetic acid (from the HMT pathway) have little activity and are excreted in the urine.
DAO is the most important enzyme in histamine metabolism, but it is only found in certain tissues: the intestinal mucosa, kidneys, placenta, thymus and seminal vesicles. It also plays a small role in liver tissue. It is mainly located in the intestinal epithelium, the area where histamine is absorbed and degraded by DAO, representing itself as a modulator of its passage into the bloodstream. DAO located in the liver controls the passage of histamine into the systemic circulation and, when found in the kidney, degrades histamine reabsorbed in the proximal tubule.
Other biological functions of diamine oxidase
Histamine-rich foods
Table of rich-histamine foods (histamine content in mg/kg): aubergine 26, avocado pear 23, red wine 13, white wine 21, sparkling wine 6,3, bottle beer 2, cured meats (beicon, sausage, fuet, majorcan sausage) 350, cooked meat (ham) 5, champagne 67, fermented white cabbage (xucrut) 10-200, spinach 20-30, wheat and rice flour 5, goat cheese 87,1, cured cheese 162,1, emmental cheese 10-500, fresh cheese 5, grated cheese 556,4, roquefort cheese 2.000, yogurt 13, legumes (lentils, chickpeas and beans) 10, raw milk 389,9, mushrooms 1,8, cured meats (cured ham) 10, fresh meat (beef, pork) 4, beans 2, pasturized milk 162, olives 2, blue fish semipreserves 1.500, fresh fish 19,75, fresh blue fish (tuna, sardines) 10, frozen fish 894, fresh and frozen blue fish 2, fermented vegetable products (soya derived) 2.300, fruit juice 1,5, tomato (fresh, sauce) 0,5-8, vinegar 500, apple cicler vinegar 20, balsamic vinegar 4.000, chocolat 0,5.
There are discrepancies on the criteria to consider a food rich or not in histamine.
Some authors propose eliminating from diet food with concentrations above 20 mg/kg, while others are much more demanding and consider foods with low levels of histamine to contain less than 1 mg/kg. What is clear is that the symptomatologic dose is much lower in histaminosis than in toxicity: 15-20mg and 150mg respectively, as the tolerable dose is 100mg/kg in both cases.
Traditionally, the study of histamine content has focused on foods associated with episodes of histamine poisoning, such as oily fish, but this is a mistake as the mechanism of increased histamine levels in these foods is different. These are sporadic outbreaks in the general population, because of the unhygienic effects of food.
Nevertheless, there are some initiatives in Europe (ALBA, ALlergen dataBAnk; TNO Nutrition and Food Research) to have a comprehensive data bank on histamine content in foods, due to the decarboxylation of its precursor amino acid, histidine. The disadvantage of these data is that they can vary widely from one food to another: The concentrations of histamine and other biogenic amines in foods vary widely within a food family and even from sample to sample of the same product.
When comparing the same food from different sources, none of the values match, as the amount of histamine varies according to the degree of fermentation in each case. This is why it is so difficult to set a specific value for each food. For the same reason it is very difficult to keep only those foods containing a maximum of 20 mg/kg in the diet, as all foods contain histamine and can influence the values.
Foods that are easily microbiologically spoiled, such as meat and fish, or foods and beverages produced by fermentation or maturation, can be considered as susceptible to high histamine values.
Foods rich in other amines
In addition to histamine-rich foods, high intakes of foods rich in other amines such as
putrescine, cadaverine, b-phenylethylamine, tryptamine, serotonin, tyramine and agmatine can also lead to DAO saturation, disabling it from properly degrading histamine from histamine-rich foods in patients with low DAO activity.
Histamine’s most competitive amines for degradation by DAO are putrescine and cadaverine, as their degradation is faster than histamine’s and they engage the enzyme before.
The presence of amines can vary in each type of food, as is the case with histamine. Depending on the greater or lesser presence of biogenic amines, foods with the same amount of histamine may or may not cause symptoms.
Even so, there are established amounts for amines in general, indicating the maximum tolerable level at which symptoms do not occur, but they only refer to toxicity; values relating to the intake of amine-rich foods to DAO saturation have not yet been established. Endogenous histamine releasing foods.
This group includes foods which, without having a high concentration of histamine or other amines, releases endogenous histamine, i.e., the histamine located in the mast cells.
Some foods have been described as having this characteristic: egg white, milk (particularly milk protein) and some cereals.
It has also been reported that some food additives can release endogenous histamine, such as glutamate, benzilate, some colorants (yellow E-102 and E-110, red E-124, amarante E-123), sulphites and nitrites.
The ingestion of endogenous histamine-releasing foods or drugs causes the same symptoms as the ingestion of histamine-rich foods.
