METABOLISM OF METHYLHISTAMINE FORMED THROUGH A NEW PATHWAY: DECARBOXYLATION OF L-3-METHYLHISTIDINE

¹ Unité de Neurobiologie de l’I.N.S.E.R.M Höpital Sainte-Anne, Paris, France

Biosynthesis of methylhistamine (MHA) may occur in part by a pathway which does not involve histamine (HA) transmethylation: ³H-MHA was isolated by ion-exchange chromatography followed by solvent extraction and identified by thin-layer chromatography from several tissue extracts of mice previously injected with tracer doses of the natural amino acid ³H-^l-3-methylhistidine (MeHis). Tissues, such as the stomach, which synthesized ³H-MHA at the highest rate were also capable of highest decarboxylation of ³H-histidine (³H-His). ³H-MHA formation in the stomach of ³H-MeHis-injected mice was markedly reduced after pretreatment with nonradioactive l-His (500 mg/kg) or with the histidine decarboxylase inhibitor, brocresine (200 mg/kg). Experiments with rat stomach supernatant confirmed that the specific His decarboxylase was probably responsible for MeHis decarboxylation: ³H-MHA formation was not affected by 10^-4 M -methyldopa but was inhibited by 10^-4 M brocresine and was highly reduced in extracts from food-deprived rats. Moreover, ³H-His and ³H-MeHis were found to compete mutually for this enzyme, but the affinity of MeHis (Km = 9 x 10^-3 M) was lower than that of His (K_m = 3 x 10^-4 M). ³H-MHA synthesized from ³H-MeHis was released by treatments known to induce endogenous HA release: this was the case for these aminmes from mouse stomach after food intake or vagal stimulation induced by insulin as well as from rat peritonmeal mast cells after in vitro addition of compound 48/80. MeHis loading (1000 mg/kg) in mice resulted in significant reductions in ³H-HA formatiom in the stomach and in endogenous HA levels in brain. Since MeHis is known to be normally present in plasma and tissues, our results indicate that HA and MHA are synthesized and stored in the same sites from which they may be released together under physiological or pathological conditions.

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