Histamine metabolism

Stimulation of HDC activity by hormones and other events produces a small, non-mast cell, inducible histamine pool in tissues (Oh et al., 1988 Aoi et al., 1988). This de novo histamine production is stimulated under a variety of immunological and physical stresses (Schayer, 1962 Nandi et al., 1974 Clemetson, 1980 Nakano and Suzuki, 1984). Additionally, in the human brain, histaminergic neurons are a source of histamine (Schwartz et ai, 1991) as well as resident mast cells. 

Low blood histamine levels are observed during pregnancy (Clemetson, 1980), a reflection of increased histamine catabolism by placental DAO (Bardsley et al.. 

1974 Baylin and Margolis, 1975). In human carcinomas, DAO activity is increased (Baylin et al., 1975 Chanda and Ganguly, 1987), but tissue histamine levels are generally elevated due to the high histamine production by tumors (Maslinski et al., 1984 Chanda and Ganguly, 1987). The main route of histamine metabolism in man is methylation, in the presence of HMT, to methylhistamine, which is subsequently deaminated by monoamine oxidase to form methylimidazole acetic acid (Fig. 1) (Beaven, 1976 Keyzer a/., 1984). 

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Histamine synthesis in the brain is controlled by the availability of L-histidine and the activity of histidine decarboxylase 254 Histamine is stored within and released from neurons but a neuronal transporter for histamine has not been found 254 In the vertebrate brain, histamine metabolism occurs predominately by methylation 254... 

Biosynthesis is performed in one step by the enzyme L-histidine decarboxylase (HDC, E.C. 4.1.1.22). Histamine metabolism occurs mainly by two pathways. Oxidation is carried out by diamine oxidase (DAO, E.C. 1.4.3.6), leading to imidazole acetic acid (IAA), whereas methyla-tion is effected by histamine N-methyltransferase (HMT, E.C. 2.1.1.8), producing fe/e-methylhistamine (t-MH). IAA can exist as a riboside or ribotide conjugate. t-MH is further metabolized by monoamine oxidase (MAO)-B, producing fe/e-methylimidazole acetic acid (t-MIAA). Note that histamine is a substrate for DAO but not for MAO. Aldehyde intermediates, formed by the oxidation of both histamine and t-MH, are thought to be quickly oxidized to acids under normal circumstances. In the vertebrate CNS, histamine is almost exclusively methylated... 

The product of histamine methylation, t-MH, is a substrate for MAO-B and is ultimately oxidized to t-MIAA, the end product of brain histamine metabolism. Thus, MAO... 

Taylor, S. and Lieber, E.R. (1979). In vitro inhibition of rat intestinal histamine-metabolizing enzymes. Food Cosmet. Toxicol., 17, 237. 

Since the majority of an oral dose of histamine is excreted as various histamine metabolites, the metabolism of histamine probably serves as a detoxification mechanism. As noted earlier, the small intestine and liver are particularly active in histamine metabolism and would be expected to protect against the toxicity of orally administered histamine. 

The hypothesis that histamine toxicity could be potentiated by inhibition of histamine-metabolizing enzymes was supported by early experiments that demonstrated a potentiation of histamine- induced contractions of smooth muscle by inhibitors of DAO (22.23). 

However, these experiments were not directed at the oral toxicity of histamine. Taylor and Lieber ( ) showed that rat intestinal HMT and DAO could be inhibited iri vitro by certain amines, including some putrefactive amines that are known to occur in spoiled fish (46.47). Many of these amines inhibited only one of the two histamine-metabolizing enzymes, but several including cadaverine and aminoguanidine were effective inhibitors of both HMT and DAO (45). Mixtures of the inhibitors were not tested, but would be predicted to be quite effective in inhibiting intestinal histamine metabolism. 

However, as shown in Table II, the ratio of histamine to its metabolites was altered substantially by the presence of cadaverine and aminoguanidine. In the presence of these substances, more unmetabolized histamine reached the serosal fluid indicating that inhibition of intestinal histamine metabolism had been effective in potentiating the uptake of histamine. Anserine was ineffective. 

Further research will be necessary to demonstrate conclusively that inhibition of histamine metabolism is responsible for the potentiation of histamine toxicity that is apparently observed in scombroid poisoning. In vivo experiments will be necessary to show that hepatic histamine metabolism is also compromised by the ingestion of suspected potentiators. Also, the effectiveness of cadaverine and other possible potentiators must be demonstrated under conditions where the histamine level exceeds the potentiator concentration by a factor of approximately 10. This concentration ratio would parallel that found in spoiled tuna more closely than the levels used in the experiments of Lyons et al. (48). 

The inactivation of histamine is achieved both by enzymatic metabolism of the amine and by transport processes that reduce the concentration of the compound in the region of its receptors. Histamine metabolism occurs primarily through two pathways (Fig. 38.1). The most important of these involves histamine N-methyltransferase, which catalyzes the transfer of a... 

An alternative pathway of histamine metabolism involves oxidative deamination by the enzyme diamine oxidase (histaminase) to form 5-imidazoleacetic acid. Diamine oxidase is present in both tissues and blood and plays a particular role in metabolizing the large concentrations of histamine that may be present in food. An additional metabolite, A-acetyl histamine (a conjugate of acetic acid and histamine), can be produced if histamine is ingested orally. This product may result from metabolism of histamine by gastrointestinal tract bacteria. Because of its rapid breakdown after oral administration, histamine produces few systemic effects when given by this route. 

Histamine metabolism differs from that of classical neurotransmitters because histamine is so widely distributed in the body. The highest concentrations in human tissues are found in the lung, stomach, and skin (upto 33 ug/g tissue). Histamine metabolic pathways are simple histamine is produced from histidine in just one step (see figure 4.11). The principal production takes place in the mast cells of the peritoneal cavity and connective tissues. The gastric mucosa is another major storage tissue. Histamine can be found in the brain as well. 

Imidazoleacetic acid riboside Figure 4.11 Histamine metabolism. 

L-Tyrosine metabolism and catecholamine biosynthesis occur laigely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andUpid metabolism. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bile acids and the detoxification process of aromatic drugs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabolism related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

DIAMINE OXIDASE INHIBITORS act on the non-selective enzyme diamine oxidase (histaminase), which has as substrate such diverse substances as histamine, cadaverine and putrescine. As with the monoamine-oxidase enzyme, an intermediate complex is formed to yield the aldehyde, and this is then oxidized. The enzyme has been studied in relation to histamine metabolism, and is found to be released in certain circumstances from eosinophils and other tissues, and can be used as a marker in thyroid and ovarian carcinoma. Blood levels are raised in pregnancy, and heparin raises these levels. Amounts of the enzyme are high in the intestinal mucosa, liver and kidney of most species, A preparation of the enzyme itself (Torantil ) was once available for use in therapeutics for conditions in which a deficiency of histamine was implicated. 

Oral ingestion of up to 1 mmol (ca. 100 mg) of histamine does not elicit toxic symptoms in normal individuals (Motil and Scrimshaw, 1979). However, vasodilation and increased heart rate result on intravenous administration of 0.07 /imol, demonstrating the importance of histamine-metabolizing enzymes in the digestive tract. More research is needed to define nontoxic levels of histamine in foods which may contain other substances that potentiate the action of histamine, e.g., putrescine and cadaver-ine (Bjeldanes etal., 1978). Construction of an overall biogenic amine index may be valuable for the establishment of regulatory fimits (Joosten, 1988). 

Hui, J. Y., and Taylor, S. L. (1985). Inhibition of in vivo histamine metabolism in rats by foodborne and pharmacologic inhibitors of diamine oxidase, histamine iV-methyltransfer-ase and monoamine oxidase. Toxicol. Appl. Pharmacol. 81, 241-249. 

Noncompetitive antagonist of histamine Physiologic antagonist of histamine Chemical antagonist of histamine Metabolic inhibitor of histamine... 

This enzyme is a pyiidoxal phosphate protein, which has been called histaminase since it catalyses a reaction which is one of the main pathways of histamine metabolism. It may be assayed ladiochemically using labelled cadaverine [350] or by deamination of labelled histamine to form tiitiated water [351]. 

P. S.J. Spencer and G.B.West, Thyroid-adrenocortical Antagonism and Histamine Metabolism, Nature, Lond. 199, 1298-1299 (1963). 

Gas Chromatographic Analysis of Histamine Metabolism in Urine. Quantitative Determination of Ring-Methylated Imidazole-Acetic Acids in Healthy Man... 

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