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Regulation of Uridine Diphosphate Glucuronosyltransferase Expression by Phenolic Antioxidants¹

Department of Medicine, Cornell University Medical College and the Strang Cancer Prevention Center, New York, New York 10021 [K. K., E. K. Y., A. J. D.], and the Department of Medicine and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461 [J. R. C., N. R. C.]

Dietary antioxidants protect laboratory animals against the induction of tumors by a variety of chemical carcinogens. Among possible mechanisms, 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, butylated 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-glucuronosyltransferase activities in liver microsomes for p-nitrophenol (236 and 218%, respectively), 3-hydroxybenzo(a)pyrene (246 and 175%, respectively), and androsterone (269 and 152%, respectively). Immunoblots showed changes in the amounts of UDP-glucuronosyltransferase isoforms corresponding to the changes in enzyme activities. Northern blot analysis showed that the concentration of UDP-glucuronosyltransferase mRNA paralleled the concentration of enzyme proteins and their respective levels of enzyme activity. BHT, for example, caused about a 250% increase in mRNA using a probe that recognizes the common 3'-domain of bilirubin/phenol UDP-glucuronosyltransferase mRNAs. In addition to inducing hepatic enzyme activities, BHT and BHA increased the activity of UDP-glucuronosyltransferase in the small intestine and kidney.

¹ This work was partly supported by NIH Grants 1K08 DK1992, T32 DK07142, RO1-DK 39137 and RO1-DK 46057. Additional support was obtained from the International Life Sciences Institute Research Foundation.

² To whom requests for reprints should be addressed, at Division of Digestive Diseases, Room F-231, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021.

Received 6/15/94. Accepted 9/16/94.

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