title: In vivo and in vitro inhibition of human histidine decarboxylase by (S)-alpha-fluoromethylhistidine.
abstract: Histidine decarboxylase (HDC) activity in Ficoll-Hypaque purified human peripheral blood leukocytes (PBL) was determined by measuring the formation of [3H]histamine from L-[3H]histidine. HDC activity was inhibited in vitro to more than 90% by (S)-alpha-fluoromethylhistidine (alpha-FMH) at concentrations of 10(-5) M and above. Both polymorphonuclear and mononuclear cells possessed HDC activity, but on a per cell basis the former had several-fold higher enzyme activity than the latter. In safety and tolerability studies, alpha-FMH was administered orally to healthy human subjects twice daily for 7 days at doses of 2.5, 10, 50 and 100 mg per person. A dose-dependent inhibition of HDC activity was observed in PBL that were isolated both at 12 hr after administration of the first dose of alpha-FMH and after treatment for 1 week. At the 50 and 100 mg doses of alpha-FMH, there was complete inhibition of HDC activity and partial inhibition at the 10 mg dose. Twenty-four hours after the last dose, HDC activity had recovered to 64-100%, 44-46%, and 30-52% of control values in subjects that received 10, 50 and 100 mg alpha-FMH respectively.
mesh_terms: D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D006632:Histamine / Q000378:metabolism; D006639:Histidine / Q000031:analogs & derivatives* / Q000378:metabolism; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D007962:Leukocytes / Q000201:enzymology*; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008762:Methylhistidines / Q000494:pharmacology*; D009000:Monocytes / Q000201:enzymology; D009504:Neutrophils / Q000201:enzymology
chemical_list: D008762:Methylhistidines; D006639:Histidine; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D002262:Carboxy-Lyases; D006640:Histidine Decarboxylase