BHT and Related Alkylphenols Historical Overview

The contributions of QMs to the toxicities of the food additive BHT and structurally related alkylphenols in rats and mice have been investigated extensively over the past 25 years. This work has generated considerable insight into the relationships between toxicity and the metabolic formation and reactivity of these electrophiles. Most studies have focused on liver and lung damage is primarily observed in these organs due, 

SCHEME 10.2 Common pathways of QM formation in biological systems, (a) Stepwise two-electron oxidation by cytochrome P450 or a peroxidase, (b) Enzymatic oxidation of a catechol followed by spontaneous isomerization of the resulting n-quinone. (c) Enzymatic hydrolysis of a phosphate ester followed by base-catalyzed elimination of a leaving group from the benzylic position. 

Witschi and colleagues19 identified the requirement for metabolic activation of BHT in determining that radioactivity from 14C-labeled BHT became covalently bound to proteins in mouse lung. Both toxicity and protein binding were prevented when mice were treated with cytochrome P450 inhibitors, thereby indicating the 

SCHEME 10.3 Direct oxidation of BHT to BHT-QM by rats and mice, and a mouse-specific BHT hydroxylation followed by QM formation. 

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