TY - JOUR
T1 - The regulation of UDP-glucuronosyltransferase genes by tissue-specific and ligand-activated transcription factors
AU - Mackenzie, Peter
AU - Hu, Dong Gui
AU - Gardner-Stephen, Dione
PY - 2010/2
Y1 - 2010/2
N2 - Elucidation of the mechanisms regulating UGT genes is of prime importance if the adverse effects of interactions between drugs primarily eliminated by glucuronidation are to be minimized, and if UGT expression is to be manipulated for therapeutic effect. The factors controlling UGT gene expression in the liver include the liver-enriched transcription factors, HNF-1α and HNF-4α, several members of the nuclear-receptor family (CAR, PXR, FXR, LXR, and PPAR), the arylhydrocarbon receptor, and transcription factors involved in stress responses (Nrf2, Maf). HNF-1α, in concert with the intestine-specific transcription factor, Cdx2, and Sp1 regulate UGT gene expression in the gastrointestinal tract, whereas the genes for the major androgen-glucuronidating enzymes, UGT2B15 and UGT2B17, are upregulated by estrogens in breast cell lines and downregulated by androgens in prostate-derived cells. Despite this knowledge, the complex interactions between these transcription factors and their coregulators has not been determined, and the mechanisms regulating UGT gene expression in organs and tissues, other than the liver, gastrointestinal tract, breast, and prostate, remain to be elucidated.
AB - Elucidation of the mechanisms regulating UGT genes is of prime importance if the adverse effects of interactions between drugs primarily eliminated by glucuronidation are to be minimized, and if UGT expression is to be manipulated for therapeutic effect. The factors controlling UGT gene expression in the liver include the liver-enriched transcription factors, HNF-1α and HNF-4α, several members of the nuclear-receptor family (CAR, PXR, FXR, LXR, and PPAR), the arylhydrocarbon receptor, and transcription factors involved in stress responses (Nrf2, Maf). HNF-1α, in concert with the intestine-specific transcription factor, Cdx2, and Sp1 regulate UGT gene expression in the gastrointestinal tract, whereas the genes for the major androgen-glucuronidating enzymes, UGT2B15 and UGT2B17, are upregulated by estrogens in breast cell lines and downregulated by androgens in prostate-derived cells. Despite this knowledge, the complex interactions between these transcription factors and their coregulators has not been determined, and the mechanisms regulating UGT gene expression in organs and tissues, other than the liver, gastrointestinal tract, breast, and prostate, remain to be elucidated.
KW - Gene regulation
KW - Liver-enriched transcription factors
KW - Nuclear receptors
KW - UDP glucuronosyltransferase genes
UR - http://www.scopus.com/inward/record.url?scp=74549178738&partnerID=8YFLogxK
U2 - 10.3109/03602530903209544
DO - 10.3109/03602530903209544
M3 - Review article
VL - 42
SP - 99
EP - 109
JO - Drug Metabolism Reviews
JF - Drug Metabolism Reviews
SN - 0360-2532
IS - 1
ER -