Diamine oxidase (DAO), also known as histaminase, is a crucial enzyme involved in the metabolism of biogenic amines, especially histamine. DAO plays an essential role in maintaining histamine homeostasis, particularly in the gastrointestinal tract. In recent years, DAO has drawn significant attention due to its implications in allergic reactions, food intolerances, and inflammatory disorders. As a leading enzyme supplier, Creative Enzymes provides DAOs sourced from Pisum sativum and porcine kidney. In this article, we delve into the function, regulation, and clinical relevance of DAO in histamine metabolism.

The Biochemistry of Diamine Oxidase

Diamine oxidase (DAO), also referred to as histaminase, is a copper-dependent enzyme belonging to the amine oxidase family. It plays a crucial role in the oxidative deamination of diamines, particularly histamine, which is one of its principal physiological substrates. The enzymatic reaction results in the formation of imidazole acetaldehyde, ammonia (NH₃), and hydrogen peroxide (H₂O₂) through the following reaction:

R-CH₂-NH₂ + H₂O + O₂ → R-CHO + NH₃ + H₂O₂

This biochemical transformation serves as a significant detoxification mechanism, especially in tissues exposed to exogenous sources of histamine, such as the gastrointestinal tract. DAO facilitates the inactivation of histamine prior to its absorption into the systemic circulation, thereby preventing potential histamine-mediated adverse effects.

DAO is predominantly expressed in the small intestine, kidneys, and placenta, with intestinal enterocytes representing a major site of synthesis. Notably, DAO exerts its activity in the extracellular compartment, distinguishing it from histamine-N-methyltransferase (HNMT), an intracellular enzyme that inactivates histamine via methylation. HNMT catalyzes the methylation of histamine, using S-adenosylmethionine (SAM) as the methyl donor. The product, N-methylhistamine, is further metabolized by monoamine oxidase (MAO) to produce N-methylimidazole acetaldehyde, which is then converted to N-methylimidazole acetic acid. HNMT is primarily expressed in the liver and is the major histamine degradation pathway in the brain. This pathway is also linked to the availability of SAM and the synthesis of polyamines, folates, and methionine recycling.

Figure 1. Histamine metabolism in humans. DAO: diamine oxidase; HNMT: histamine-N-methyltransferase; ALDH: aldehyde dehydrogenase; MAO: monoamine oxidase. (Comas-Basté et al., 2021)

The Role of DAO in Histamine Regulation

Histamine is a multifunctional biogenic amine involved in various physiological processes, including the regulation of gastric acid secretion, modulation of immune responses, and neurotransmission. However, excessive accumulation of histamine—whether due to increased endogenous production or exogenous dietary intake—can result in a range of pathological symptoms, including flushing, headaches, gastrointestinal disturbances, hypotension, and other manifestations resembling allergic reactions.

Figure 2. Histamine is involved in multiple physiological processes. (Moya-García et al., 2021)

DAO plays an essential role in the degradation of dietary histamine, which is found in a variety of histamine-rich foods such as aged cheeses, fermented products, certain fish, and alcoholic beverages. By metabolizing histamine within the intestinal lumen, DAO serves as a biochemical barrier, limiting histamine absorption and maintaining its plasma concentration within physiologically safe thresholds. This protective function underscores the enzyme's importance in histamine homeostasis.

Histamine Intolerance

Histamine intolerance is a condition characterized by an imbalance between the accumulation and degradation of histamine, often due to deficient diamine oxidase activity. This imbalance leads to a buildup of histamine in the body, resulting in symptoms that resemble those of IgE-mediated allergic reactions but occur without allergen-specific immune responses. The symptoms of histamine intolerance are diverse and can affect multiple systems in the body, including the gastrointestinal tract, skin, respiratory system, and nervous system.

Symptoms of Histamine Intolerance

Histamine intolerance can cause a wide range of symptoms, which may vary from person to person. Common symptoms include:

• Gastrointestinal Issues: Bloating, abdominal pain, gas, diarrhea, constipation, nausea, and vomiting.
• Skin problems: Itching, flushing, hives, eczema, and rosacea.
• Respiratory Symptoms: Nasal congestion, sneezing, runny nose, and difficulty breathing.
• Cardiovascular Symptoms: Palpitations, irregular heartbeat, low blood pressure, and dizziness.
• Neurological Symptoms: Headaches, migraines, anxiety, irritability, and mood swings.
• Other Symptoms: Menstrual irregularities, heavy periods, and sleep disturbances.

Causes of DAO Deficiency

DAO deficiency can be congenital or acquired, and it is a major contributing factor to histamine intolerance. Common causes of DAO deficiency include:

• Genetic factors: Certain genetic mutations can lead to reduced DAO enzyme production.
• Medications: Various drugs, including NSAIDs (e.g., aspirin, ibuprofen), antibiotics, antidepressants, and antihistamines, can inhibit DAO activity.
• Nutritional Deficiencies: A lack of essential nutrients such as vitamin B6, vitamin C, zinc, or copper can impair DAO function.
• Alcohol Consumption: Alcohol inhibits DAO, leading to increased histamine levels.
• Gastrointestinal Disorders: Conditions such as Crohn's disease, ulcerative colitis, celiac disease, and SIBO (small intestinal bacterial overgrowth) can damage the intestinal lining and reduce DAO production.
• Hormonal Fluctuations: Changes in estrogen and progesterone levels, particularly during the menstrual cycle, can affect DAO activity.

Figure 3. The causes of HIT. The red drop with H represents the histamine. The etiology of HIT is mainly related to genetic polymorphisms of DAO or HNMT, diseases associated with DAO or HNMT deficiency, dysbacteriosis, drugs that inhibit DAO activity, foods that are rich in histamine, foods that inhibit DAO, and foods that promote histamine release. (Zhao et al., 2022)

Management of Histamine Intolerance

In clinical practice, dietary management is the primary intervention for treating histamine intolerance. It typically involves adopting a low-histamine diet to reduce the intake of histamine-rich foods and alleviate symptoms. Common high-histamine foods include wine, beer, avocados, nuts, milk, soybeans, mushrooms, chocolate, shellfish, eggs, oily fish, strawberries, and pineapples. Some individuals may also benefit from DAO supplements, which help break down dietary histamine.

In such cases, DAO supplementation—typically in the form of oral tablets derived from porcine or plant-based sources—has shown promise in mitigating symptoms by enhancing the breakdown of dietary histamine. However, the efficacy of supplementation varies among individuals, and clinical trials are ongoing to establish standardized treatment protocols.

Diagnosis and Testing

Diagnosing histamine intolerance can be challenging due to the nonspecific nature of its symptoms. However, a thorough medical history and symptom assessment are essential for identifying potential triggers and managing the condition. While serum DAO levels can provide some indication of DAO activity, they are not always reliable for diagnosing histamine intolerance. Instead, a low-histamine diet trial is often recommended to observe symptom improvement.

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In summary, diamine oxidase is a key regulator in histamine metabolism, particularly relevant in the gastrointestinal context. Its ability to degrade histamine efficiently makes it a vital component in preventing histamine-related pathologies. Understanding the factors that affect DAO activity and its clinical implications enables more precise diagnosis and management of conditions such as histamine intolerance.

Creative Enzymes provides a wide selection of premium enzymes and extracts, including high-quality DAO enzymes. Contact us with any inquiries or custom requests!