Oxidative metabolism of the GABAA receptor antagonist t-butylbicycloortho[3H]benzoate.

1. The trioxabicyclooctane ring of t-butylbicycloortho[3H]benzoate (TBOB), (CH3)3CC(CH2O)3CC6H5, is cleaved to yield the 3-oxo-benzoate, (CH3)3CC(CHO)(CH2OH)CH2OC(O)C6H 5, on O-methylene hydroxylation by microsomes from mouse liver or houseflies in the presence of NADPH.2. The methyl and phenyl substituents are tentatively identified as additional sites of oxidative metabolism.3. The 3-oxo-benzoate from oxidative cage opening and the bis-(hydroxymethyl)-benzoate, (CH3)3CC(CH2OH)CH2OC(O)C6H 5, from enzymic reduction of the 3-oxobenzoate undergo esteratic hydrolysis to benzoic acid.4. Metabolites of TBOB excreted by rats and houseflies include the bis-(hydroxymethyl)-benzoate and benzoic and hippuric acids.5. Metabolic hydroxylation of TBOB at O-methylene, alkyl and aryl substituents may serve as a model for detoxication reactions of related potent GABAA receptor antagonists and insecticides.