Inhibition of histamine synthesis in vitro and in vivo by S-alpha-fluoromethylhistidine.
(S)-alpha-Fluoromethylhistidine (alpha-FMH) is a Kcat or "suicide-substrate" inhibitor of partially purified mammalian histidine decarboxylase; i.e. the agent is converted enzymatically to a more active form which effects a time-dependent, irreversible inhibition. Incubation of a alpha-FMH[4-3H] with enzyme and pyridoxal phosphate resulted in an apparently irreversible labeling of protein, with no demonstratable formation of free-amine product, suggesting a very low to non-existent turnover ratio. alpha-FMH was accumulated in isolated mastocytoma cells and effected a time-dependent inhibition of the conversion histidine[3H]----histamine[3H], the latter product having a markedly different distribution between cells and medium than the pre-existing histamine pool. Inhibition of whole-body histidine decarboxylase activity, as specifically measured by alpha-methylhistidine-14COOH----14CO2, was also time dependent. Concomitant reduction in histamine levels was seen only in the rapidly turning-over pools of stomach and brain. However, over the course of 13 weeks of chronic treatment, depletion of the relatively inert mast-cell histamine pool(s) was seen as well.
D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D005260:Female; D006632:Histamine / Q000032:analysis / Q000096:biosynthesis*; D006639:Histidine / Q000031:analogs & derivatives*; D006640:Histidine Decarboxylase / Q000032:analysis / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D008762:Methylhistidines / Q000494:pharmacology*; D051379:Mice; D011247:Pregnancy; D051381:Rats; D013270:Stomach / Q000032:analysis
D008762:Methylhistidines; D002245:Carbon Dioxide; D006639:Histidine; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D006640:Histidine Decarboxylase