Oxidation of butylated hydroxytoluene to toxic metabolites. Factors influencing hydroxylation and quinone methide formation by hepatic and pulmonary microsomes.
The effects of inducing agents and inhibitors on the cytochrome P-450-catalyzed oxidations of butylated hydroxytoluene (BHT) to form three metabolites were investigated with liver and lung microsomes from rats and mice. These compounds, the quinone methide (QM) formed by two-electron oxidation of BHT, the hydroxy-tert-butyl analog of BHT (BHT-OH) resulting from aliphatic hydroxylation, and the hydroxy-quinone methide (QM-OH) derived from BHT-OH, have been implicated previously as intermediates or products involved in BHT bioactivation and toxicity. Although there was little or no increase in BHT metabolism in pulmonary microsomes from either species following phenobarbital (PB) administration, 6- to 37-fold enhancements occurred in the transformation of BHT to QM, and the conversion of BHT-OH to QM-OH with hepatic microsomes from both species. The first step in QM-OH formation, hydroxylation of BHT to BHT-OH, is a minor pathway with hepatic microsomes from treated or untreated rats, thereby explaining the lack of QM-OH formation from BHT by that species. The two-step oxidation of BHT to QM-OH, however, is a relatively important metabolic pathway with hepatic microsomes from PB-treated mice, due to an unusually large (111-fold) PB-induced increase in the tert-butyl hydroxylation step. These results demonstrate that pulmonary microsomes from mice, but not rats, have relatively high constitutive P-450 activity for the formation of QM-OH from BHT, supporting the proposal that this metabolite is involved in BHT-induced pneumotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Molecular Toxicology and Environmental Health Sciences Program, School of Pharmacy, University of Colorado, Boulder 80309.
J L
JL
Bolton
J A
JA
Thompson
D000818:Animals; D002084:Butylated Hydroxytoluene / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D006900:Hydroxylation; D045563:Indolequinones; D007211:Indoles / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008805:Mice, Inbred A; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011809:Quinones / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D045563:Indolequinones; D007211:Indoles; D011809:Quinones; D014230:Triazoles; C068040:quinone methide; C033020:1-aminobenzotriazole; D002084:Butylated Hydroxytoluene; D011335:Proadifen; D010634:Phenobarbital; D008797:Metyrapone