CommentaryCoordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2
Introduction
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor of the bHLH/PAS (basic helix–loop–helix/Per–Arnt–Sim) family with important roles in metabolic adaptation, in normal physiology such as organ and vascular development and dioxin toxicology [1], [2], [3]. Metabolic adaptation is achieved by coordinate regulation of a set of xenobiotic-metabolizing enzymes (XMEs), termed AhR battery [4], [5]. Coordination occurs by AhR/Arnt-binding to xenobiotic response elements (XREs, also termed dioxin response elements [DREs]), identified in the 5′ upstream region of AhR target genes [2], [6], [7]. The AhR gene battery is arguably one of the best-characterized examples of coordinately regulated genes in eukaryotes. The XRE sequence 5′-T/GnGCGTG-3′ is not symmetrical, suggesting that AhR and Arnt bind to different parts of the sequence. In vitro studies of the E-box sequence (5′-CACGTG-3′) indicated that Arnt binds to GTG; hence, AhR binds 5′ of this sequence [2], [7]. Flanking sequences most likely influence AhR binding to particular target genes. It has to be noted that a number of XRE-controlled genes/proteins have been identified which are not involved in xenobiotic metabolism, but in cell proliferation and differentiation ([3], [7], [8] for references). The AhR battery discussed here is focused on Phase I XMEs (CYP1A1, 1A2 and 1B1) and on Phase II enzymes (NQO1, GSTA2, UGT1A1 and UGT1A6), with emphasis on UGTs which are often neglected in reviews. A schematic view of XME functions is illustrated in Fig. 1. Rodent and human conjugate transporters such as MRPs and BCRP may also be members of the AhR gene battery since their expression is increased by AhR agonists, but the responsible XREs still have to be elucidated [9], [95], [96]. Notably, two definitions of Phase I and II XMEs have emerged. For example, NQO1 (and other enzymes with similar regulation such as the aldehyde dehydrogenase ALDH3A1 [3], [4], [5], the latter not discussed here) is a Phase I enzyme on the basis of the catalyzed chemical reaction, but is often regarded as Phase II enzyme on the basis of common regulation by Nrf2 [10], [11]. Among many coordinately regulated genes identified in microarray studies, characterization of functional XREs identifies the primary target genes of the AhR. In this context it is important to establish functionality since core XRE sequences may be present randomly in the genome.
It has been recognized recently that Phase II genes of the AhR gene battery are linked to a second gene battery, termed Nrf2 gene battery, which is involved in protection against oxidative stress [10], [11], [12], [13], [14], [15]. The bZip transcription factor Nrf2 binds to antioxidant response elements (AREs) in the regulatory region of a large and distinct set of target genes, including the Phase II genes NQO1, GSTA2 and UGT1A6, discussed under Section 2.2. It also includes glutamyl-cysteine synthetase (GCS, the rate limiting enzyme in the synthesis of glutathione), heme oxygenase-1 and other proteins protecting against oxidative stress. An ARE consensus sequence (5′-TG/TAC/GnnnGC-3′) has been identified [13]; but so far no universally applicable consensus sequence can be derived [16], [17]. Deficiency of both Nrf1 and Nrf2 results in early embryonic lethality due to oxidative stress [18]. Nrf2 and its function appear to be evolutionary conserved since a Nrf2-like protein (SKN-1) has been identified in Caenorhabditis elegans[19]. Linkage between AhR and Nrf2 batteries is probably achieved by multiple mechanisms in a species and cell-specific manner, discussed under Section 2.3: (i) Nrf2 is a target gene of the AhR [20]. (ii) Nrf2 can be activated indirectly by reactive oxygen species generated by induced CYP1A1 [42], [43]. (iii) In the case of NQO1, direct cross-interaction between AhR/XRE and Nrf2/ARE signaling has been proposed [14].
In the present commentary current knowledge about transcriptional regulation of Phase I and II XMEs by AhR/XRE and Nrf2/ARE signaling is reviewed and compared in rodents and humans. Functional consequences of coordinated Phase I and II enzyme regulations are discussed using detoxification of benzo[a]pyrene (BaP) quinones and catechol estrogens as examples.
Section snippets
AhR/XRE-induced xenobiotic-metabolizing enzymes (XMEs)
After brief comparison of the AhR battery in rodents and humans, linkage of AhR- and Nrf2-controlled Phase II genes is addressed. The discussion is based on selected Phase I and II genes with characterized functional XREs and/or AREs (Fig. 2). In addition, factors responsible for hormonal control and for tissue-specific expression are discussed to underline that the AhR exerts its functions in concert with many other factors.
Tightened coupling between Phase I and II metabolisms by AhR- and Nrf2, detoxification of benzo[a]pyrene quinones as example
Tight coupling of Phase I and II enzymes is expected in homeostatic control of endogenous ligands of the AhR, such as UV light generated indolocarbazole derivatives from tryptophane. This amino acid serves as a chromophore for UV light in the exposed skin. 6-Formylindolo[3,2-b]carbazole (FICZ) is formed in keratinocytes which binds to the AhR with higher affinity than TCDD [67], [68]. However, and in contrast to TCDD, FICZ is rapidly metabolized by the AhR family members CYP1A1, CYP1A2 and
Roles of AhR battery in detoxification of o-quinones, catechol estrogens as example
The AhR gene battery has also implications in preventing toxic redox cycles between catechol estrogens and o-quinones. Estradiol is hydroxylated by CYPs at many positions [86]. Whereas CYP1A1 mostly hydroxylates at C2, CYP1B1 is the major enzyme catalyzing C4 hydroxylation [87]. 4-Hydroxylated catechol estrogens are recognized as potent carcinogens due to high affinity for estrogen receptors and to ROS formation by redox cycling with o-quinones [87]. C2- and C4-hydroxylation is markedly
Conclusions
Coordinate induction of Phase I and II XMEs by the AhR and Nrf2 may greatly attenuate the accumulation of reactive intermediates generated by Phase I enzymes. These reactive intermediates, in particular reactive oxygen species, are known to modulate cell signaling and cell death in many ways [92]. In case of the discussed AhR gene battery, coordination is achieved by common DNA binding domains (XREs) for the ligand-activated AhR in the regulatory region of target genes. Note that the XRE core
References (96)
- et al.
Ah receptor: dioxin-mediated toxic responses as hints to deregulated physiologic functions
Biochem Pharmacol
(2006) - et al.
Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis
Biochem Pharmacol
(2000) - et al.
Activation of coupled Ah receptor and Nrf2 gene batteries by dietary phytochemicals in relation to chemoprevention
Biochem Pharmacol
(2006) - et al.
Identification of a variant antioxidant response element in the promoter of the human glutamate-cysteine ligase modifier subunit gene
J Biol Chem
(2002) - et al.
Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress
J Biol Chem
(2003) - et al.
Transcriptional regulation of NF-E2 p45-related factor (Nrf2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway
J Biol Chem
(2005) - et al.
Role of aryl hydrocarbon receptor-mediated induction of CYP1 enzymes in environmental toxicity and cancer
J Biol Chem
(2004) - et al.
The DNA recognition site for the dioxin–Ah receptor complex
J Biol Chem
(1988) - et al.
The human CYP1A2 gene and induction by 3-methylcholanthrene
J Biol Chem
(1994) - et al.
Isolation and characterization of the human cytochrome P450 CYP1B1 gene
J Biol Chem
(1996)
Ah receptor regulation of mouse Cyp1B1 is additionally modulated by a second novel complex that forms at two AhR response elements
Toxicol Appl Pharmacol
Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus
J Biol Chem
Transcriptional regulation of the rat NAD(P)H:quinone reductase gene
J Biol Chem
Antioxidant response element-mediated 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induction of human NADP(H):quinone oxidoreductase 1 gene expression
Biochem Pharmacol
Genetic regulation of bilirubin-UDP-glucuronosyltransferase induction by polycyclic aromatic compounds and phenobarbital in mice
J Biol Chem
Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1
J Biol Chem
Regulation of human UGT1A1 gene by nuclear receptors constitutive active/androstane receptor, pregnane X receptor, and glucocorticoid receptor
Meth Enzymol
Serotonin glucuronidation by Ah receptor- and oxidative stress-inducible human UDP-glucuronosyltransferase (UGT) 1A6 in Caco-2 cells
Biochem Pharmacol
Xenobiotic responsive element-mediated transcriptional activation in the UDP-glucuronosyltransferase family 1 gene complex
J Biol Chem
Transcriptional activation of the UDP-glucuronosyltransferase 1A7 gene in rat liver by aryl hydrocarbon receptor ligands and oltipraz
J Biol Chem
Contribution of the Ah receptor to phenolic antioxidant-mediated expression of human and rat UDP-glucuronosyltransferase UGT1A6 in Caco-2 and rat hepatoma 5 L cells
Biochem Pharmacol
Coordinate regulation of UDP-glucuronosyltransferase UGT1A6 induction by 3-methylcholanthrene and multidrug resistance protein MRP2 expression by dexamethasone in primary rat hepatocytes
Biochem Pharmacol
Regulation of UDP glucuronosyltransferases in the gastrointestinal tract
Toxicol Appl Pharmacol
Intralobular distribution of UDP-glucuronosyltransferase in livers from untreated, 3-methylcholathrene- and phenobarbital-treated rats
Chem Biol Interact
Induction of UDP-glucuronosyltransferase and aryl hydrocarbon hydroxylase activity in mouse skin and normal and transformed skin cells in culture
Biochem Pharmacol
Mono- and diglucuronide formation of benzo[a]pyrene and chrysene diphenols by AHH-1 cell expressed UDP-glucuronosyltransferase UGT1A7
Biochem Pharmacol
Formation of mono- and diglucuronides and other glycosides of benzo[a]pyrene-3,6-quinol by V79 cell-expressed human phenol UDP-glucuronosyltransferases of the UGT1 gene complex
Biochem Pharmacol
Ah receptor-controlled transcriptional regulation of rat and human UDP-glucuronosyltransferase isoforms
Adv Enzyme Regul
Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1,1A3, and 2B7
Toxicol Sci
Uptake and efflux transporters for conjugates in human hepatocytes
Meth Enzymol
2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity
Ann Rev Pharmacol Toxicol
The PAS superfamily: sensors of environmental and developmental signals
Ann Rev Pharmacol Toxicol
P450 genes: structure, evolution, and regulation
Ann Rev Biochem
Induction of cytochrome P4501A1
Ann Rev Pharmacol Toxicol
The aryl hydrocarbon receptor complex
Ann Rev Pharmacol Toxicol
Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries
Mol Pharmacol
Induction of multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver
Drug Metab Dispos
Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice
Proc Natl Acad Sci USA
Powerful and prolonged protection of human retinal pigment epithelial cells against oxidative damage: the indirect oxidant effects of sulforaphane
Proc Natl Acad Sci USA
Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray
Cancer Res
Regulatory mechanisms controlling gene expression mediated by the antioxidant response element
Ann Rev Pharmacol Toxicol
Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires CNC (cap ‘n’ collar) basic leucine zipper factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction
Biochem J
Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence
Biochem J
Regulation of the Caenorrhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase 3
Proc Natl Acad Sci USA
A DNA-binding factor specific for xenobiotic response elements of P-450c gene exists as a cryptic form in cytoplasma: its possible translocation to nucleus
Proc Natl Acad Sci USA
The Ah-receptor: genetics, structure and function
Pharmacogenetics
Functional analysis of the human cytochrome P4501A1 (CYP1A1) gene enhancer
Eur J Biochem
A common regulatory region functions bidirectionally in transcriptional activation of the human CYP1A1 and CYP1A2 genes
Mol Pharmacol
Cited by (287)
Natural Allies for Heart Health: Nrf2 Activation and Cardiovascular Disease Management
2024, Current Problems in CardiologyPersistent organic pollutants (POPs) in marine crustaceans: Bioaccumulation, physiological and cellular responses
2023, Marine Environmental ResearchThe complex biology of aryl hydrocarbon receptor activation in cancer and beyond
2023, Biochemical PharmacologyThe effects of environmental aryl hydrocarbon receptor ligands on signaling and cell metabolism in cancer
2023, Biochemical Pharmacology