CommentaryAh receptor- and Nrf2-gene battery members: Modulators of quinone-mediated oxidative and endoplasmic reticulum stress
Graphical abstract
Introduction
Quinones and their phenolic precursors are ubiquitously present in animals and their environment. They include polyphenols and tocopherols in the diet, drugs in medicine, and metabolites of environmental pollutants. Quinones are involved in diverse biologic processes such as electron transport, metabolism of estrogens and catecholamines, and detoxification of aromatic hydrocarbons. Quinone–quinol redox cycles lead to oxidative stress, and some quinones are highly toxic arylating agents, reacting with cellular thiols. Thereby, they activate pathophysiologic processes such as endoplasmic reticulum (ER) stress, inflammation and cancer ([1], [2], [3] for references).
Enzyme systems have evolved to detoxify reactive quinones such as multiple glutathione S-transferases (GSTs) [4], [5], and the NAD(P)H:quinone oxidoreductases NQO1 and NQO2. The latter enzyme converts quinones by 2-electron reduction to corresponding quinols. Quinols are subsequently conjugated by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) [6]. Detoxification enzymes are often termed drug-metabolizing enzymes (DMEs) due to their importance in drug development and therapy. Early studies suggested that benzo[a]pyrene (BaP)-3,6-quinone after reduction to the corresponding quinol, was efficiently detoxified by Ah receptor (AhR)-regulated rat UGT1A6 (in the early publication termed UGT1A1) together with an at that time unknown UGT, now designated rat UGT1A7 [7], [8], and by human UGT1A6 and UGT1A9 (the latter termed UGT1.7 in the early publication) [9]. NQO1, UGTs and GSTs are also controlled by the antioxidant Nrf2-Keap1 pathway, in addition to regulation by the AhR [10], [11], [12], [13]. Recently, it has been established that both AhR and Nrf2 are required for the induction of these enzymes in mice [14] and possibly humans [15].
It was the aim of the commentary to emphasize two AhR- and Nrf2-regulated pathways which attenuate quinone-mediated oxidative and ER stress: (i) GSTs acting together with glutathione biosynthesis, and (ii) NQO1 and NQO2 acting together with UGTs and SULTs. Tight coupling between these enzymes is necessary to prevent chronic oxidative and ER stress which may lead to tissue-dependent toxicity, exemplified by BaP toxicity in enterocytes, catecholestrogen-mediated genotoxicity in breast tissue and endometrium, and aminochrome-mediated oxidative stress in neurons and astrocytes of substantia nigra.
Section snippets
Overview of Ah receptor- and Nrf2-regulated gene batteries
AhR is the only ligand-activated member of the bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) family of transcription factors [16]. It represents a multifunctional switch involved, for example, in female reproduction, vascular development, inflammation, immunosuppression, and adaptive detoxification of lipophilic endo- and xenobiotics [16], [17]. Notably, AhR controls both basal and adaptive DME expression [18]. After ligand binding the AhR translocates to the nucleus, sheds chaperones and
Detoxification of quinones by GSTs
GSTs are multifunctional enzymes, mainly involved in detoxification of ROS and other electrophiles, including metabolites of lipid peroxidation, epoxides and quinones [4], [5]. They are present as cytosolic, mitochondrial and microsomal enzymes. Multiple classes of cytosolic GSTs have been characterized, such as GSTA, M and P members, which are expressed in a cell-dependent manner.
In addition to GSTs, GSH homeostasis is also regulated by Nrf2, for example, the rate limiting enzymes of GSH
Quinone detoxification by NQO1 and NQO2 acting together with UGTs and SULTs
Quinones can be reduced (i) by 1-electron transfer pathways to semiquinones, for example, by CYP reductase, leading to semiquinone/quinone redox cycles and oxidative stress, or (ii) by 2-electron transfer, bypassing the semiquinone step via the multifunctional cytosolic flavoprotein NQO1 [6], [35]. In support of its detoxification function, a polymorphism of NQO1 in humans (4% in Caucasians and 20% in Chinese) leads to rapid degradation of the enzyme, and has been associated with increased risk
Examples of cell-dependent quinone reductase-coupling with conjugation
Paradoxical effects have been observed when extrapolating in vitro effects of Phase I metabolism to the in vivo situation. The reason was discussed as tight coupling between Phase I and II metabolism [48]. The degree of Phase I and II coupling is expected to be cell specific and depends upon the pharmacokinetics of the particular chemical, as subsequently discussed.
Consequences of quinone-mediated oxidative and ER stress
As indicated in the introduction, exposure of cells to arylating quinones may trigger the ER stress response [1]. The ER is involved in processing secretory and integral membrane proteins, for example, in chaperone-mediated protein folding by forming the correct SS-bonds. Obviously, the latter function is impaired by covalent binding of arylating quinones to cellular thiols. The resulting ER stress response, also termed unfolded protein response, is initiated by activation of three protein
Therapeutic approaches involving Ah receptor and Nrf2 modulation
AhR- and Nrf2-regulated genes/enzymes are attractive since they can be modulated, for example, by phytochemicals. Phytochemical activators and inhibitors of AhR include DIM (diindolylmethane, the biologically active oligomer of indole-3-carbinol) and resveratrol, respectively. These AhR modulators and activators of Nrf2 such as sulforaphane and epigallocatechin gallate are currently studied in preclinical trials of chemoprevention [77]. In addition, coffee has been demonstrated to induce AhR-
Conclusions
Quinones are involved in physiologic processes but they are also toxic compounds. Quinone–quinol redox cycles produce oxidative stress, and chronic exposure to arylating quinones may produce ER stress with resulting apoptosis or inflammation. Therefore, detoxifying enzymes evolved to prevent tissue injury. Two pathways are emphasized: (i) GSTs and GSH biosynthesis, and (ii) NQO1 and NQO2 acting together with UGTs and SULTs. Interestingly, these pathways are induced by activating both AhR and
Acknowledgement
I thank Christoph Köhle for preparing the figures.
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