Histamine Intolerance: Why the DAO Enzyme Story Is Incomplete, and the Real Reason Your Low Histamine Diet Stopped Working — The Two Breakdown Enzymes

The standard story discusses DAO. It rarely mentions HNMT, the second histamine breakdown enzyme. The two enzymes handle different pools of histamine through different mechanisms, and the difference is clinically important. DAO (Diamine Oxidase) DAO is an extracellular enzyme. It is produced primarily by enterocytes in the small intestine and is secreted into the gut lumen, where it acts on histamine before it can be absorbed. DAO is also present in the placenta (which is why DAO levels rise dramatically in pregnancy and many women with histamine intolerance experience temporary remission while pregnant) and in plasma at lower levels. DAO is the principal regulator of dietary histamine and of histamine in the gut. DAO requires three cofactors: vitamin B6 (pyridoxal phosphate), copper, and vitamin C. Deficiency in any of these reduces DAO activity. Several medications inhibit DAO including some antibiotics, some antidepressants (especially MAOIs), some anti inflammatory drugs, and verapamil. Genetic variants in the AOC1 gene (the gene encoding DAO) reduce DAO activity in carriers. DAO addresses gut histamine. It does not address tissue histamine. It does not address central nervous system histamine. It does not address bacterial histamine that is produced and acts at the mucosal level if local DAO is insufficient or if the production rate exceeds the breakdown rate. HNMT (Histam