Histidine decarboxylase inhibiting and histamine lowering effects of 2-hydroxy-5-carbomethoxybenzyloxyamine have been studied in detail. The compound proved to be a potent inhibitor of both rat stomach pyloric histidine decarboxylase and guinea-pig liver aromatic l-amino acid decarboxylase, showing a more pronounced effect on the former enzyme. The type of inhibitions were ascribed as reversible and competitive with respect to substrate and coenzyme in both cases. The Ki values for histidine and pyridoxal phosphate were 1 × 10-7 and 2.5 × 10-7M; for5-hydroxytryptamine and pyridoxal phosphate, 1 × 10-6 and 5 × 10-6 M. Studies with the pyridoxal phosphate oxim of this substance showed no remarkable inhibition of the nonspecific enzyme, and substantially less effect on specific decarboxylase than that obtained with 2-hydroxy-5-carbomethoxybenzyloxyamine itself. These results suggested that the inhibiting effect of the compound is partly directly on the coenzyme, forming a pyridoxal phosphate inactivator complex, but mainly on the apoenzyme, displacing pyridoxal phosphate from the apoenzyme. The fact that the inhibitory activity of the compound mainly depended on the relative strength of binding of pyridoxal phosphate to apoenzyme, showing substantially less effect on aromatic l-amino acid decarboxylase and on diamine oxidase than that on histidine decarboxylase, confirmed this assumption. Administration of the inhibitor to male rats resulted in lower levels of histamine in stomach, lungs, heart and skin. The minimum effective dose of the compound was 15 mg/kg maximal effects were obtained with doses of 45 mg/kg in lungs, heart and skin and 135 mg/kg in stomach. The maximal effects were observed 1-2 hr after the treatment and were significantly less at 5 hr. Repeated administration resulted in lower histamine levels than after single treatments. No toxic effects were apparent during repeated and prolonged administrations of the inhibitor.
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