Understanding the relationship between nuclear receptors and drug metabolizing enzymes (DMEs) is important because it is closely associated with the metabolism of endogenous and xenobiotic compounds as well as drug-drug interactions. This study is divided into two parts : 1) the creation of a PXR transgenic mouse model and 2) the regulation of the UDP-glucuronosyltransferase 1A (UGT1A) locus through activation of the liver x receptor [alpha] (LXR[alpha]). The transgenic mouse line that contains the human pregnane X receptor (hPXR) transgene was established and the PXR transgene was determined to be functional by elevated levels of cytochrome p450 3a11 (Cyp3a11) in response to hPXR activator rifampicin. Crossing this transgenic mouse line with the mouse line Tg(UGT1A1*1)Ugt- /-Pxr-/- (hUGT1*1/Pxr-/-) line, previously established in the lab, we created a Tg(UGT1A1*1)Ugt-/-Tg(Pxr)Pxr-/- (hUGT1*1/hPXR) mouse line. For the second aim of this study, humanized UGT1A (hUGT1) mice were administered the LXR agonist, T090137, and the results show a significant induction of UGT1A1 in the liver and intestinal tissues compared with the control mice, suggesting that the LXR[alpha] regulates the UGT1A locus. These results are further supported by a significant reduction of serum bilirubin levels in response to T090137 treatment. Work is ongoing to create Lxr[alpha]-null mice on a hUGT1A background (hUGT1/- Lxr-/ mice). In conclusion, these two mice lines, hUGT1*1/hPXR and hUGT1A/Lxr[alpha]-/-, are potentially useful to study the roles of PXR and LXR in the UGT1A locus regulation that may have significant implications in altering glucuronidation activity of xenobiotics and endogenous compounds, including bilirubin