Diamine oxidase

Diamine oxidase (DAO), also known "amine oxidase, copper-containing, 1" (AOC1), formerly called histaminase, is an enzyme involved in the metabolism, oxidation, and inactivation of histamine and other polyamines such as putrescine or spermidine. The enzyme belongs to the amine oxidase (copper-containing) (AOC) family of amine oxidase enzymes.

The enzyme is expressed in bilateria, a biological group of animals. The enzyme is encoded by the AOC1 gene. This gene is highly conserved across the bilateria group which includes mammals, birds, reptiles, fish and insects, to name a few.

Chemical activity
DAO catalyzes the oxidative deamination of polyamines, such as histamine and putrescine, to produce aminoaldehydes, hydrogen peroxide, and ammonia.

DAO metabolizes histamine into imidazole-4-acetaldehyde:


 * $$\mathrm{R{-}CH_2{-}NH_2 + H_2O + O_2 \longrightarrow R{-}CHO + NH_3 + H_2O_2}$$

Biological role
DAO is involved in the physiology of digestion and other physiological processes, such as inflammation, immune response, and wound healing. Dysfunction of DAO has been associated with various diseases, including allergies, autoimmune disorders, and cancer. DAO also plays a role in healthy pregnancy in placental mammals.

In case of a shortage or low enzymatic activity of diamine oxidase in the human body, it may appear as an allergy or histamine intolerance.

Expression
In placental mammals, including humans, the highest levels of DAO expression are observed in the digestive tract (intestinal mucosa) and the placenta. DAO expression is also observed in kidney of various species.

DAO is also expressed in eosinophils.

The role in human pregnancy
In humans, a certain subtype of cells of the placenta, namely the extravillous trophoblasts, express the enzyme and secrete it into the blood stream of a pregnant woman.

During pregnancy, DAO plays a crucial role in maintaining fetal growth and development by regulating histamine levels. DAO levels in the blood circulation increases vastly in pregnant women suggesting a protective mechanism against adverse histamine. Histamine is a potent vasodilator and can cause uterine contractions, which can lead to premature labor. DAO in the placenta breaks down histamine to prevent its accumulation and maintain a healthy pregnancy. Low levels of DAO in the placenta may contribute to preeclampsia, a pregnancy-related disorder characterized by mother's high blood pressure and damage to mother's organs such as the liver and kidneys; the baby may also be affected if the condition is severe or left untreated, but it is not the primary target of the disorder.

Lowered diamine oxidase values in maternal blood in early pregnancy might be an indication for trophoblast-related pregnancy disorders like early-onset preeclampsia.

Supplementation
Exogenous DAO (supplements) are being studied as complementary treatment for the relief of symptoms associated with histamine intolerance, and for the relief of other conditions, such as migraine or fibromyalgia. However, the results are inconclusive because studies to date have involved small study populations and short intervention periods.

In the United States, DAO supplements are available over the counter but are not FDA-approved.

In Europe, two investigations, financially backed by the manufacturer of the oral DAO supplementation, have posited that DAO supplementation could alleviate patient symptoms. The first study sought to "objectify and quantify histamine-associated symptoms and to analyze whether oral administration of the histamine-degrading enzyme DAO caused a reduction of symptoms". In this study, neither major nor minor symptoms could be replicated in 39 patients who initially responded to an open challenge with 75 mg histamine in peppermint tea, using a double-blind, placebo-controlled challenge. Consequently, the primary endpoint of the study was not achieved, and the basis for the authors' conclusion that DAO supplementation intake resulted in a "statistically significant reduction in symptoms" remains unclear. The second study was purely observational, lacking a control group: it compared symptomatology with and without DAO use in 28 patients. The chosen design was not suitable to demonstrate causal effects and carried a high risk of attributing placebo effects. The effectiveness of DAO supplementation has not been scientifically validated and is not recommended by the medical associations in Germany, Austria and Switzerland.

Research directions
DAO is related on possible links to migraine conditions. During migraine episodes, there is a noted elevation in the plasma concentrations of both calcitonin gene-related peptide (CGRP) and histamine. These substances are known for their potent vasodilatory effects and have been observed to mutually stimulate each other's release within the trigeminovascular system, potentially contributing to the onset of migraines, so that individuals with genetic variants in the DAO gene often experience migraines when consuming a diet high in histamine. As such, exploring the functional interplay between exogenous histamine and CGRP could provide valuable insights into the mechanisms underlying diet-induced migraines. This area of research continues to be actively investigated.