REGULATION OF URIDINE-DIPHOSPHATE GLUCURONOSYLTRANSFERASE EXPRESSION BY PHENOLIC ANTIOXIDANTS

Dietary antioxidants protect laboratory animals against the induction of tumors by a variety of chemical carcinogens. Among possible mechani sms, protection against chemical carcinogenesis could be mediated via antioxidant-dependent induction of detoxifying enzymes. Therefore, we investigated the effects of two commonly used food preservatives, buty lated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), on the expression of UDP-glucuronosyltransferase isoforms in rat liver. Male Wistar rats were fed a control diet or diets containing BHA (0.75%) or BHT (0.5%) for 2 weeks. BHT and BHA increased UDP-glucuronosyltransfe rase activities in liver microsomes for p-nitrophenol (236 and 218%, r espectively), 3-hydroxybenzo(a)pyrene (246 and 175%, respectively), an d androsterone (269 and 152%, respectively). Immunoblots showed change s in the amounts of UDP-glucuronosyltransferase isoforms corresponding to the changes in enzyme activities. Northern blot analysis showed th at the concentration of UDP-glucuronosyltransferase mRNA paralleled th e concentration of enzyme proteins and their respective levels of enzy me activity. BHT, for example, caused about a 250% increase in mRNA us ing a probe that recognizes the common 3'-domain of bilirubin/phenol U DP-glucuronosyltransferase mRNAs. In addition to inducing hepatic enzy me activities, BHT and BHA increased the activity of UDP-glucuronosylt ransferase in the small intestine and kidney.