Interaction between Oxidative Stress Sensor Nrf2 and Xenobiotic-activated Aryl Hydrocarbon Receptor in the Regulation of the Human Phase II Detoxifying UDP-glucuronosyltransferase 1A10

Abstract

The defense against oxidative stress is a critical feature that prevents cellular and DNA damage. UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation of xenobiotics, mutagens, and reactive metabolites and thus act as indirect antioxidants. Aim of this study was to elucidate the regulation of UGTs expressed in the mucosa of the gastrointestinal tract by xenobiotics and the main mediator of antioxidant defense, Nrf2 (nuclear factor erythroid 2-related factor 2). Xenobiotic (XRE) and antioxidant (ARE) response elements were detected in the promoters of UGT1A8, UGT1A9, and UGT1A10. Reporter gene experiments demonstrated XRE-mediated induction by dioxin in addition to tert-butylhydroquinone (ARE)-mediated induction of UGT1A8 and UGT1A10, which are expressed in extrahepatic tissue in humans in vivo. The responsible XRE and ARE motifs were identified by mutagenesis. Small interfering RNA knockdown, electrophoretic mobility shifts, and supershifts identified a functional interaction of Nrf2 and the aryl hydrocarbon receptor (AhR). Induction of UGT1A8 and UGT1A10 requires Nrf2 and AhR. It proceeds by utilizing XRE-as well as ARE-binding motifs. In summary, we demonstrate the coordinated AhR-and Nrf2-dependent transcriptional regulation of human UGT1As. Cellular protection by glucuronidation is thus inducible by xenobiotics via AhR and by oxidative metabolites via Nrf2 linking glucuronidation to cellular protection and defense against oxidative stress.

Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain

“…UGTs play important roles in the detoxification of xenobiotics, including drugs and environmental substances, protecting the organism from the effects of hazardous compounds. UGTs also function as antioxidants in their role of maintaining the redox balance (Kalthoff et al, 2010). Compared with other organs, the brain appears especially susceptible to excessive oxidative stress (Dringen et al, 2000;Bergamini et al, 2004).…”

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…In support of these findings, experiments using AhR-deficient and -proficient rat hepatoma 5L cells suggest that AhR is necessary for induction by tertbutylhydroquinone, a prototypical activator of Nrf2-Keap1 signaling [31]. In humans, UGT1 members also appear to be regulated by both AhR and Nrf2 [43,89].…”

Secondary Plant Metabolites for Sun Protective Cosmetics: From Pre-Selection to Product Formulation

“…There is also growing evidence that the physiological role of AhR in the skin is not limited to xenobiotic metabolism, but it extends to numerous functions of cutaneous cells such as breakdown of endogenous metabolites, proliferation, cell-to-cell contacts, immune and inflammatory responses, and melanogenesis [56]. Among the endogenous AhR ligands identified so far, there are the products of tryptophan photo-oxidation, squalene photo-oxidation, oestrogen, prostaglandins, bilirubin/biliverdin, and kinurenic acid [32,57,58]. Apart from metabolic enzymes, a number of growth factors, cytokines, chemokines and their receptors are down-stream gene targets for activated AhR [45,59].…”