UDP-glucuronosyltransferases (UGTs) represent major phase II
enzymes of
drug metabolism which are regulated in a tissue-specific manner by endogenous and environmental factors. Among the latter,
aryl hydrocarbon receptor (AhR) agonists such as
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD) and phenolic
antioxidants such as
tert-butylhydroquinone (
tBHQ) are known to induce the expression of
human UGT1A6 in Caco-2 cells. While binding of the
TCDD-activated AhR to one
xenobiotic response element (XRE) in the 5'-flanking regulatory region of UGT1A6 was characterised previously, the mechanism responsible for
tBHQ induction is unknown. Therefore, it was investigated whether antioxidant response elements (AREs) are involved in
tBHQ induction of UGT1A6. Transfectants of 3 kb of its regulatory region and its deletion mutants were treated with
tBHQ. These studies suggested a region with approximately 2-fold induction, including an ARE-like motif, 15 bp downstream of the previously characterised XRE. Transfectants of the point-mutated ARE-like motif showed marginally reduced response to
tBHQ, but surprisingly, loss of response to
TCDD, suggesting interference of flanking
proteins with the AhR/Arnt complex. Coordinate responses of UGT activity
after treatment with
TCDD or
tBHQ were also observed in rat
hepatoma 5L cells, mutants without the AhR and with recomplemented AhR. The results suggest a contribution of the AhR pathway and of
proteins binding to the XRE flanking region to the induction of
human UGT1A6 by both AhR agonists and phenolic
antioxidants.