3.1.4.4 Glucocorticoid Activation A glucocorticoid response element was
identified near the CAR/PXR binding site in human UGT1A1 (Sugatani, 2005).
Low concentrations of dexamethasone enhanced PXR activation of this gene
when the glucorticoid receptor and GRIP1 were coexpressed into HepG2 cells.
3.1.4.5 Peroxisome Proliferator–Activated Receptor (PPAR) Activation
Clofibrate, ciprofibrate, WY-14643, perfluorodecanoate:
Fibrates are relatively specific inducers of bilirubin glucuronidation
(UGT1A1), UGT1A3, and UGT1A9 (Barbier, 2003).
3.1.4.6 Antioxidant Response Element (ARE) UGTs are upregulated by
treatment with a number of chemopreventative agents such as sulforphane.
This occurs through the formation of reactive electrophilic metabolites that
bind to selected cysteine residues in the cytosolic sensor protein Keap1.
Upon adduction of these cysteines, Kea1p is signaled for ubiquination
resulting in the release of the orphan transcription factor Nrf2. Nrf2 is
transported to the nucleus where it binds to antioxidant response elements in a
wide number of genes including heme oxygenase, NQO1 (quinone reductase),
glutathione-S-traneferases (GSTs) that play a protective role in oxidative
damage via elimination of these metabolites. Ritter and coworkers found no
TABLE 3.2 (Continued)
UGT1
gene Species
Endogenous
substrates Tissue expression CommentsUGT2B12 Rat Liver, kidney,
intestine
UGT2B13 Rabbit 17 b-Estradiol
(low)
Adult liver 4-Hydroxybiphenyl
is selective
substrate. 66%
identical to rat
UGT2B1
UGT2B14 Rabbit Estriol Adult liver 73% identical
to UGT2B13
UGT2B15 Human Testosterone,
dihdydro-
testosterone
Liver, prostate,
testes, esophagusUGT2B16 Rabbit
UGT2B17 Human Testosterone,
androsterone
Liver, kidney,
prostate, testes,
uterus, placenta,
mammary glands,
adrenals, skin
UGT2B18 Monkey
UGT2B19 Monkey
UGT2B20 Monkey
UGT2B21 Guinea pig
UDP-GLUCURONOSYLTRANSFERASES 45