Bioactivation of 2,6-Di-Tert-Butyl-4-Methyl Phenol (BHT) and Hydroxylated Analogues to Toxic Quinoid Metabolites
Phenolic antioxidants produce a variety of effects in animals. For example, butylated hydroxytoluene (BHT) has either anticarcinogenic or tumor promoting activity, depending on the dosing regimen (Malkinson, 1983). BHT also produces acute pulmonary toxicity in mice (Witschi et al., 1989) and hepatotoxicity in rats (Mizutani et al., 1987), and these effects are believed to be due to its oxidative biotransformation to reactive metabolites. As shown in Figure 1, mouse liver and lung cytochrome P-450’s catalyze the metabolism of BHT along three pathways: (A) hydroxylation of the 4-methyl group (forming BHT-MeOH), (B) hydroxylation of a tert-butyl group (forming BHT-OH) and (C) oxidation of the pi-electron system to a phenoxy radical that leads to quinoid products (Thompson et al., 1987). Loss of a second electron from this radical generates the quinone methide (BHT-QM), and combination with molecular oxygen yields the peroxyquinol (BHT-PQ) that is rapidly degraded by P-450 to a variety of products (Wand and Thompson, 1986).
KeywordsIntramolecular Hydrogen Bonding Mouse Lung Butylate Hydroxy Toluene Reactive Metabolite Phenoxy Radical
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