Inhibition of histamine synthesis in brain by alpha-fluoromethylhistidine, a new irreversible inhibitor: in vitro and in vivo studies.
alpha-Fluoromethylhistidine (alpha-FMH), a new potent inhibitor of histidine decarboxylase (HD), has been used for in vitro and in vivo studies of brain HD. Following a preincubation with (+)-alpha-FMH, brain HD activity was inhibited in a time-dependent and concentration-dependent manner. The enzyme activity was not restored by overnight dialysis against standard buffer. The (-) antimer of alpha-FMH was ineffective. When injected intraperitoneally in a single dose of 20 mg/kg, (+/-)-alpha-FMH induced a complete loss in HD activity in cerebral cortex and hypothalamus as well as in peripheral tissues, such as stomach. At a dosage of 100 mg/kg (+/-)-alpha-FMH did not alter histamine-N-methyltransferase, DOPA decarboxylase, and glutamate decarboxylase activities. The maximal decrease of HD activity occurred after 2 h in both cerebral cortex and hypothalamus, but the time course of the recovery of enzyme activity was slower in the cerebral cortex. The enzyme activity reached control value within 3 days in hypothalamus and was not fully restored after 4 days in cerebral cortex. Contrasting with the diminished HD activity, a substantial concentration of histamine remained present in five regions of mouse brain. Thus, alpha-FMH is a highly specific irreversible inhibitor of brain HD activity and its efficacy makes it useful to study the physiological role of brain histamine.
D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors; D006632:Histamine / Q000096:biosynthesis*; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors; D006639:Histidine / Q000031:analogs & derivatives*; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors*; D008297:Male; D008762:Methylhistidines / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D008762:Methylhistidines; D006639:Histidine; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D006637:Histamine N-Methyltransferase; D002262:Carboxy-Lyases; D005968:Glutamate Decarboxylase; D006640:Histidine Decarboxylase