Disposition of Histamine, Its Metabolites, and pros‐Methylimidazoleacetic Acid in Brain Regions of Rats Chronically Infused with α‐Fluoromethylhistidine

Abstract

In mammalian brain, histamine is known to be metabolized solely by histamine methyltransferase (HMT), forming te/e-methylhistamine (t-MH), then telemethylimidazoleacetic 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]histaminewas given intracerebroventricularly 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 a-fluoromethylhistidine (a-FMHi5), 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 corresponded 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-M IAA 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 a-FMHis infusion as a model to probe the histaminergic system in brain.

Modulation of the histaminergic system and behaviour by α‐fluoromethylhistidine in zebrafish

“…This could also include an aggregation of existing HA vesicles. Another possibility is that there is an effective re‐uptake system for HA when the availability of the transmitter is restricted and the HA methyltransferase levels are low (Prell et al . 1996a).…”

Imidazoleacetic acid-ribotide: An endogenous ligand that stimulates imidazol(in)e receptors

“…Bovine brain CDS (42), human cerebrospinal fluid, and rat brain extracts (12,13) were eluted from Dowex-AG-acetate columns (1-3 N acetic acid) and analyzed by HPLC (43). Authentic IAA-ribotides ( Fig.…”

“…The former is likely to be the main pathway in the CNS, because there, histamine is mainly methylated. In addition, regional CNS levels of IAA (G.D.P., unpublished data) correlated with those of histidine transaminase (also termed kynurenine aminotransferase) (10) but not with those of histamine or its synthetic enzyme, and inhibition of histamine synthesis did not markedly affect IAA levels (11)(12)(13). Pulse-chase studies showed IAA could be conjugated with phosphoribosyl-pyrophosphate (while hydrolyzing ATP) to produce an IAA-ribotide (14)(15)(16)(17).…”

4′-{[2-(But-2-enyl)-4-chloro-5-formyl-1H-imidazol-1-yl]methyl}biphenyl-2-carbonitrile

“…Imidazole-4acetic acid is a catabolite of histamine and is present in the brain (Prell et al, 1996), and an imidazole succinic acid complex is an active non-steroidal aromatase inhibitor (Schiavo et al, 1988). It also acts as a ligand that will bind readily to a metal ion in aqueous systems.…”