Elsevier

Biochemical Pharmacology

Volume 73, Issue 12, 15 June 2007, Pages 1853-1862
Biochemical Pharmacology

Commentary
Coordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2

https://doi.org/10.1016/j.bcp.2007.01.009Get rights and content

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with important roles in metabolic adaptation, normal physiology and dioxin toxicology. Metabolic adaptation is based on coordinate regulation of a set of xenobiotic-metabolizing enzymes (XMEs), termed AhR battery. Coordination is achieved by AhR/Arnt-binding to XREs (xenobiotic response elements), identified in the 5′ upstream region of AhR target genes. The AhR battery encodes Phase I and II enzymes. Interestingly, these Phase II genes are linked to the Nrf2 gene battery that encodes enzymes that are essential in protection against oxidative/electrophile stress. Nrf2 binds to AREs (antioxidant response elements) in the regulatory region of a large and distinct set of target genes. Functionally characterized response elements such as XREs and AREs in the regulatory region of target genes may provide a genetic basis to understand AhR- and Nrf2-induced genes. Linkage between AhR and Nrf2 batteries is probably achieved by multiple mechanisms, including Nrf2 as a target gene of the AhR, indirect activation of Nrf2 via CYP1A1-generated reactive oxygen species, and direct cross-interaction of AhR/XRE and Nrf2/ARE signaling. Linkage appears to be species- and cell-dependent. However, mechanisms linking XRE- and ARE-controlled Phase II genes need further investigation. Tightened coupling between Phases I and II by AhR- and Nrf2-induced XMEs may greatly attenuate health risks posed by CYP1A1-generated toxic intermediates and reactive oxygen species. Better recognition of coordinate Phase I and II metabolisms may improve risk assessment of reactive toxic intermediates in the extrapolation to low level endo- and xenobiotic exposure.

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

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