Disposition of histamine, its metabolites, and pros-methylimidazoleacetic acid in brain regions of rats chronically infused with alpha-fluoromethylhistidine.
In mammalian brain, histamine is known to be metabolized solely by histamine methyltransferase (HMT), forming tele-methylhistamine (t-MH), then tele-methylimidazoleacetic acid (t-MIAA). We previously showed that imidazoleacetic acid (IAA), a GABA agonist, and histamine's metabolite in the periphery, is present in brain where its concentration increased after inhibition of HMT. Also, when [3H]histamine was given intracerebro-ventricularly to rats, a portion was converted to IAA, a process increased by inhibition of HMT. These results indicated that brain has the capacity to oxidize histamine but did not show whether this pathway is operative under physiological conditions. To address this question, rats were infused for > 4 weeks with alpha-fluoromethylhistidine (alpha-FMHis), an irreversible inhibitor of histamine's synthetic enzyme, L-histidine decarboxylase. Compared with controls (untreated and saline-treated rats), brain levels of histamine, t-MH, and t-MIAA in all regions were markedly reduced in treated rats. As a percentage of controls, depletion of t-MIAA > t-MH > histamine in all regions, and regional depletions of histamine co-responded to its turnover rates in regions of rat brain. In contrast, levels of IAA were unchanged as were levels of pros-methylimidazoleacetic acid, an isomer of t-MIAA unrelated to histamine metabolism. Results suggest that in brains of rats, unlike in the periphery, most IAA may not normally derive from histamine. Because histamine in brain can be converted to IAA under certain conditions, direct oxidation of histamine may be a conditional phenomenon. Our results also support the existence of a very slow turnover pool of brain histamine and use of chronic alpha-FMHis infusion as a model to probe the histaminergic system in brain.
Prell
G D
GD
Department of Pharmacology, Mount Sinai School of Medicine of the City University of New York, New York, USA.
Douyon
E
E
Sawyer
W F
WF
Morrishow
A M
AM
D000818:Animals; D001921:Brain / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism*; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000378:metabolism*; D007260:Infusion Pumps; D008297:Male; D008761:Methylhistamines / Q000378:metabolism; D008762:Methylhistidines / Q000008:administration & dosage* / Q000494:pharmacology; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
D007093:Imidazoles; D008761:Methylhistamines; D008762:Methylhistidines; C002667:methylimidazoleacetic acid; C055224:pros-methylimidazoleacetic acid; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D006640:Histidine Decarboxylase; C020404:tele-methylhistamine