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)C6H5, 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)2CH2OC(O)C6H5, from enzymic reduction of the 3-oxo-benzoate 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.
Scott
J G
JG
Department of Entomological Sciences, University of California, Berkeley 94720.
Palmer
C J
CJ
Casida
J E
JE
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism* / Q000652:urine; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D004355:Drug Stability; D005243:Feces / Q000032:analysis; D006793:Houseflies / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013045:Species Specificity
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D011963:Receptors, GABA-A; C046308:tert-butylbicyclo-2-benzoate