Kidneys of pregnant mice synthesize histamine when incubated in the presence of carnosine, manganese, and pyridoxal phosphate. Intensity of biosynthesis increases linearly with the amount of enzyme and the incubation time. The reaction can only be catalysed by two enzymes that are located in kidneys and act in succession: carnosinase, which hydrolyzes carnosine into its two moieties, and histidine decarboxylase, which transforms histidine, a product of carnosine degradation, into histamine. The biosynthesis of histamine from carnosine seems to increase with the progress of pregnancy. In nonpregnant mice, kidneys do not effect this biosynthesis. The above results directly demonstrate that carnosine may be used for histamine synthesis when the activity of histidine decarboxylase is high, as in pregnant mouse kidney. Vertebrate carnosine, its role still enigmatic, might thus be mainly a potential histidine reservoir that would be mobilized any time there is a significant requirement for histidine, such as for histamine biosynthesis.
Carcinine was biosynthesized by Carcinus maenas from [14C]beta-alanine, [14C] histidine and [14C] histamine. Since carnosine (beta-alanyl-histidine) could not be detected in crab tissues, biosynthesis of carcinine could only be effected by direct coupling of beta-alanine and histamine resulting from histidine decarboxylation. Biosynthesis of carcinine was weak when [14C]beta-alanine and [14C] histidine were used as precursors. On the contrary when [14C] histamine was used, synthesis was important. Thus carcinine appears to be a product of histamine catabolism. After injecting [14C] histamine, radioactive carcinine was concentrated mainly in the heart and nervous system; nonmetabolized [14C] histamine was recovered mainly in the latter. The nervous system might therefore be the seat of carcinine biosynthesis and thus the site of action of histamine.
1.-- Synthesis of carcinine was performed by direct condensation of beta-alanine with histamine (free base), in the presence of N-N'-dicyclocarbodiimide. The amine radical of beta-alanine was protected by the t-butoxycarbonyl radical. This fast and simple method yielded a perfectly pure crystalline product. 2.-- Carcinine had no influence upon heartbeat frequency nor on respiratory movements in rats. 3. -- Carcinine had a vasodepressive action upon Vertebrates. It was active at half the concentration of carnosine and at about a thousand times the concentration of histamine. It appeared that histamine lost a great extent of its activity when linked with beta-alanine.
The central nervous system of Carcinus maenas synthesizes radioactive histamine when incubated in the presence of [14C] histidine and pyridoxal-5' phosphate. This biosynthesis increases linearly as a function of the amount of enzyme and the incubation time. It is not effected by heart, muscle or hepatopancreas extracts nor by haemolymph. Thus histamine appears to be synthesized mainly in the nervous system. The latter is also the seat of carcinine (beta-alanylhistamine) biosynthesis. Since carcinine seems to be a product of histamine neutralization, histamine metabolism should take place in its entirety in the nervous system. Thus histamine appears to be implicated in the neuronal activity of Carcinus. Different areas of the crustacean central nervous system: brain, eyestalks and thoracic ganglionic mass biosynthesize and metabolize histamine. Thus they all could contain sites of action for histamine. The nervous systems of two other Decapodes, Cancer and Astacus also effect histamine biosynthesis but don't metabolize it into carcinine.
Histamine neutralization in Carcinus maenas is not ensured by oxidation, methylation, or acetylation. After injecting labelled histamine, radioactive carcinine (beta-alanylhistamine), biosynthesized in the central nervous system, rapidly accumulates in the heart. This synthesis is intense and proportional to the amount of histamine injected; on the contrary, it is very low after injecting labelled beta-alanine, whatever the amount injected. Ten days after injecting [14C]histamine, the amounts of radioactive carcinine stocked in the heart remain high. When incubated in the presence of labelled carcinine, various Carcinus tissues are unable to metabolize it. Thus it appears that carcinine would be the catabolite of histamine in Carcinus maenas and that beta-alanylation would be a novel pathway for histamine neutralization. Since carcinine synthetase activity is very high in the central nervous system, this enzyme might neutralize not only neuronal histamine, but also possibly exogenous histamine; thus it would constitute an element of the blood-brain barrier.
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