5-Fluoromethylornithine (5-FMOrn) is the first specific irreversible inhibitor of L-ornithine:2-oxoacid aminotransferase (OAT) found. Single doses (greater than 10 mg/kg) of this compound inactivate OAT to a residual OAT-like activity. This activity (10-20% of total activity) is resistant to further inactivation by higher or repeated doses of 5-FMOrn, or incubation with the inactivator in vitro. Ornithine concentrations are greatly enhanced in various tissues, and urinary ornithine is dramatically increased, but no other amino acid is affected after acute treatment with 5-FMOrn. Repeated administration decreases carnosine and homocarnosine concentrations in brain. Toxic effects were not observed. The new inactivator is considered as a tool in the establishment of functions of OAT under physiological and pathological conditions.
The objective of the present study was to compare the effects of elevation of GABA concentration and those of inactivation of L-ornithine: 2-oxoacid aminotransferase (OAT) on the in vivo metabolism of L-ornithine (Orn) in brain. Vigabatrin (4-aminohex-5-enoic acid) and gabaculine (5-amino-1,3-cyclohexadienyl carboxylic acid), two well known inactivators of GABA-T, were used to elevate brain GABA concentrations. The latter inactivates OAT also. Transamination of Orn is, from a quantitative point of view, a significant reaction in mouse brain. GABA is a feed-back regulator of OAT. Within GABAergic neurons Orn concentration may be regulated by endogenous GABA. Extensive inactivation of OAT causes a considerable increase of Orn concentration, both in synaptosomes and in non-synaptosomal compartments. The results are compatible with a role of Orn as precursor of glutamate and/or GABA in certain neurons.
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