Comparative metabolism of BHA, BHT and other phenolic antioxidants and its toxicological relevance

Following oral administration, butylated hydroxyanisole (BHA) is absorbed and rapidly excreted by the rat, rabbit and man, with little evidence of long-term tissue storage. The major metabolic pathways for BHA are conjugation (phase 2) reactions, oxidative metabolism (O-demethylation) being relatively unimportant. In the dog, the extent of absorption and urinary excretion is less, and oxidative metabolism is more important than in other species. In contrast, butylated hydroxytoluene (BHT) is cleared less rapidly from most species, enterohepatic circulation being partly responsible for the delay. Tissue accumulation is also greater for BHT than for BHA. Oxidative metabolism (phase 1 reactions) mediated by the microsomal monooxygenase system is the major route for BHT degradation; oxidation of the ring methyl group predominates in the rat, rabbit and monkey, and oxidation of the tert-butyl groups in man. Gallates and 2-tert-butylhydroquinone are mainly metabolized by non-oxidative pathways (methylation or conjugation with sulphate and glucuronic acid). The different biological properties of these compounds may be related to the differences in their absorption and metabolic disposition. Thus, whereas BHT, which is metabolized by oxidation reactions, is an inducer of the microsomal mono-oxygenase system, the other phenolic antioxidants, including BHA, are only weak inducers.