Expression of the Human UGT1 Locus in Transgenic Mice by WY‐14643 and Implications on Drug Metabolism Through Peroxisome Proliferator‐Activated Receptor (PPAR) α Activation

Abstract

Transgenic mice carrying the human UDP‐glucuronosyltransferase‐1 locus (Tg‐UGT1) was recently created and shown to express the nine UGT1A genes in a pattern that resembles their expression in human tissues. In the present study, UGT1A1, 1A3, 1A4, and 1A6 have been identified as targets of PPARα in human hepatocytes and Tg‐UGT1 mice. Oral administration of WY‐14643 to Tg‐UGT1 mice led to inductionof these proteins in either the liver, gastrointestinal tract, or kidney. With UGT1A3 previously identified as the major human enzyme involved in human C24‐glucuronidation of lithocholic acid (LCA), the dramatic induction of liver UGT1A3 RNA in Tg‐UGT1 mice was consistent with the formation of LCA‐24G in plasma. Furthermore, PPAR‐responsive elements were identified flanking the UGT1A1, UGT1A3, and UGT1A6 genes by a combination of site‐directed mutagenesis, specific binding to the PPARα receptor, and functional response in HepG2 cells overexpressing PPARα. In conclusion, these results suggest that oral fibrate treatment in humans will induce the UGT1A family of proteins in the gastrointestinal tract and liver, influencing first‐pass metabolism of other drugs that are taken concurrently with hypolipidemic therapy. (Supported by USPHS grants ES10337 and GM49135).