Effects of butylated hydroxyanisole on hepatic glucuronidation capacity in mice

The present study has examined biochemical mechanisms by which butylated hydroxyanisole (BHA) increases the glucuronidation of xenobiotics. Male and female Swiss Webster mice received BHA in the diet (1% w/w) for 10 days (600 to 800 mg/kg/day). Hepatic UDP-glucuronosyltransferase activities were increased toward specific substrates in native and detergent-activated microsomes. In general, BHA increased glucuronidation toward group 1 substrates (1-naphthol and 4-nitrophenol) 36 to 141% whereas no changes were found with a group 2 (chloramphenicol) or a group 3 substrate (digitoxigenin monodigitoxoside). Also, activities toward unclassified substrates (estrone, acetaminophen, and diethylstilbestrol) were increased (29 to 139%) by BHA. BHA treatment also increased hepatic UDP-glucuronic acid content (two- to threefold) by increasing UDP-glucose concentration (30 to 50%) and enhancing UDP-glucose dehydrogenase activity (300 to 400%). BHA had a more pronounced effect in female than male mice when data were expressed as activity or amount per liver because BHA treatment selectively increased the liver weight in female mice. In conclusion, BHA increases the capacity for glucuronidation in mice by elevating both UDP-glucuronosyltransferase activities and UDP-glucuronic acid concentration in liver.