Elevation of brain GABA content by chronic low-dosage administration of hydrazine, a metabolite of isoniazid.
When gamma-aminobutyric acid aminotransferase (GABA-T) activity was measured in vitro in rat brain, neither isoniazid (INH) nor for of its known metabolites (isonicotinic acid, acetylisoniazid, acetylhydrazine, diacetylhydrazine) inhibited the enzyme in concentrations (5 mM) far higher than those likely to be achieved when INH is administered to man. In contrast, hydrazine (5 micrometers) caused a 50% inhibition of GABA-T without inhibiting glutamic acid decarboxylase (GAD). Rats were injected daily for 109 days with hydrazine (0.08 or 0.16 mmol/kg/day), after which amino acid contents and enzyme activities were measured in their brains. Both hydrazine doses caused significant elevations of whole brain GABA content and reductions of GABA-T activity, but did not affect GAD activity. Chronic administration of hydrazine at these doses did not reduce weight gain or alter rat behavior, nor did it produce any irreversible pathologic changes in liver or alterations in hepatic aryl hydrocarbon hydroxylase activity. However, hydrazine treatment caused changes in the contents of many brain amino acids besides GABA, and markedly increased concentrations of ornithine, tyrosine, and alpha-aminoadipic acid in rat plasma. Inhibition of GABA-T activity and the other biochemical alterations observed in patients given high doses of INH probably result from hydrazine formed in the metabolic degradation of INH. Thus administration of hydrazine might be a more direct means of elevating brain GABA content in patients where this seems indicated, and might not entail a greater risk of adverse effects.
D000612:4-Aminobutyrate Transaminase / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019735:Carbon-Carbon Ligases; D005260:Female; D006834:Hydrazines / Q000378:metabolism / Q000494:pharmacology*; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008025:Ligases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000596:Amino Acids; D006834:Hydrazines; C029424:hydrazine; D005680:gamma-Aminobutyric Acid; D001189:Aryl Hydrocarbon Hydroxylases; D000612:4-Aminobutyrate Transaminase; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase; D007538:Isoniazid