Antioxidants for Healthy Skin: the Emerging Role of Aryl Hydrocarbon Receptors and Nuclear Factor-Erythroid 2-Related Factor-2
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nutrients Review Antioxidants for Healthy Skin: The Emerging Role of Aryl Hydrocarbon Receptors and Nuclear Factor-Erythroid 2-Related Factor-2 Masutaka Furue 1,2,3,*, Hiroshi Uchi 1, Chikage Mitoma 1,2, Akiko Hashimoto-Hachiya 1, Takahito Chiba 1, Takamichi Ito 1, Takeshi Nakahara 1,3 and Gaku Tsuji 1,2 1 Department of Dermatology, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan; [email protected] (H.U.); [email protected] (C.M.); [email protected] (A.H.-H.); [email protected] (T.C.); [email protected] (T.I.); [email protected] (T.N.); [email protected] (G.T.) 2 Research and Clinical Center for Yusho and Dioxin, Kyushu University, Fukuoka 812-8582, Japan 3 Division of Skin Surface Sensing, Department of Dermatology, Kyushu University, Fukuoka 812-8582, Japan * Correspondence: [email protected]; Tel.: +81-92-642-5581; Fax: +81-92-642-5600 Received: 1 February 2017; Accepted: 28 February 2017; Published: 3 March 2017 Abstract: Skin is the outermost part of the body and is, thus, inevitably exposed to UV rays and environmental pollutants. Oxidative stress by these hazardous factors accelerates skin aging and induces skin inflammation and carcinogenesis. Aryl hydrocarbon receptors (AHRs) are chemical sensors that are abundantly expressed in epidermal keratinocytes and mediate the production of reactive oxygen species. To neutralize or minimize oxidative stress, the keratinocytes also express nuclear factor-erythroid 2-related factor-2 (NRF2), which is a master switch for antioxidant signaling. Notably, there is fine-tuned crosstalk between AHR and NRF2, which mutually increase or decrease their activation states. Many NRF2-mediated antioxidant phytochemicals are capable of up- and downmodulating AHR signaling. The precise mechanisms by which these phytochemicals differentially affect the AHR and NRF2 system remain largely unknown and warrant future investigation. Keywords: antioxidants; reactive oxygen species; aryl hydrocarbon receptor; nuclear factor-erythroid 2-related factor-2; phytochemicals 1. Introduction Oxidative stress is defined as an imbalance between the formation of oxidative free radicals and the antioxidant defense capacity of cells of the body [1]. Oxidative stress has been shown in many dermatological diseases, including vitiligo, atopic dermatitis, alopecia areata, photoaging, carcinogenesis, and chemotoxicity [2–12]. Most free radicals in the body exist in the form of reactive oxygen species (ROS). Excessive free radicals impair not only DNA, but also cellular proteins and lipids [9,10]. In living cells, ROS are continuously generated as a byproduct of oxidative energy metabolism to make adenosine triphosphate from glucose in mitochondria, by xanthine oxidase for the degradation of purine nucleotides, by nitric oxide synthase to make nitric oxide, and so on [10]. In addition, external stimuli, such as ionizing and ultraviolet (UV) radiation, environmental pollutants, contact allergens, and drugs, are potent inducers of ROS production [9,12–15]. Inflammatory cytokines are also responsible for ROS generation [9,10,16]. Since the skin is the outermost organ of the body, these oxidative stimulants adversely affect the proper differentiation and barrier function of the skin. One of Nutrients 2017, 9, 223; doi:10.3390/nu9030223 www.mdpi.com/journal/nutrients Nutrients 2017, 9, 223 2 of 11 the major sensors recognizing these stimulants in the skin is aryl hydrocarbon receptor (AHR), which was originally called dioxin receptor [13]. The excessive production of ROS should be neutralized or minimized by antioxidants in order to maintainNutrients skin homeostasis.2017, 9, 223 The antioxidant molecules, including glutathione, vitamin E, and2 of 11 vitamin C work together with enzymatic antioxidants, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), of the skin. One of the major sensors recognizing these stimulants in the skin is aryl hydrocarbon heme oxygenase-1 (HO-1), and glutathione S-transferase [17]. The induction of these antioxidant receptor (AHR), which was originally called dioxin receptor [13]. enzymes is regulatedThe excessive by production nuclear factor-erythroid of ROS should be 2-relatedneutralized factor-2 or minimized (NRF2), by antioxidants which is a in master order switch for antioxidantto maintain signaling skin homeostasis. [13,17]. The antioxidant molecules, including glutathione, vitamin E, and Variousvitamin phytochemicals C work together with and enzymatic herbal extracts antioxidants, exert such their as NAD(P)H:quinone antioxidant properties oxidoreductase by activating 1 the NRF2(NQO1), system heme in oxygenase an AHR-dependent‐1 (HO‐1), and glutathione or AHR-independent S‐transferase [17]. manner The induction in human of these epidermal keratinocytesantioxidant [18– 22enzymes]. Certain is regulated antioxidant by nuclear phytochemicals factor‐erythroid also 2‐related upregulate factor‐ the2 (NRF2), expression which ofis a filaggrin master switch for antioxidant signaling [13,17]. (FLG), whichVarious plays phytochemicals a pivotal role and in maintaining herbal extracts epidermal exert their antioxidant barrier function properties [19 by–21 activating,23]. the NRF2 system in an AHR‐dependent or AHR‐independent manner in human epidermal keratinocytes 2. Aryl Hydrocarbon[18–22]. Certain antioxidant Receptor Regulatingphytochemicals both also Oxidative upregulate the and expression Antioxidant of filaggrin Pathways (FLG), which AHRplays is aa xenobioticpivotal role in chemical maintaining sensor epidermal abundantly barrier expressedfunction [19–21,23]. in the epidermal keratinocytes [13,24]. Various2. external Aryl Hydrocarbon and internal Receptor ligands, Regulating such as both dioxins, Oxidative polycyclic and Antioxidant aromatic Pathways pollutants, benzo[a]pyrene, phytochemicals, and food metabolites bind to, and activate, AHR [13,24]. Tryptophan photoproduct AHR is a xenobiotic chemical sensor abundantly expressed in the epidermal keratinocytes 6-formylindolo[3,2-b]carbazole (FICZ), generated by UV irradiation, is also known as a high-affinity [13,24]. Various external and internal ligands, such as dioxins, polycyclic aromatic pollutants, endogenousbenzo[a]pyrene, ligand for phytochemicals, AHR [25,26 ].and Historically,food metabolites the bind signaling to, and pathway activate, AHR of AHR [13,24]. has been elucidatedTryptophan in studies photoproduct investigating 6‐formylindolo[3,2 the toxicity of‐b]carbazole dioxins and (FICZ), polycyclic generated aromatic by UV pollutants irradiation, [is13 ,27,28]. Upon ligationalso known by dioxins, as a high the‐affinity activated endogenous AHR ligand translocates for AHR from [25,26]. the Historically, cytoplasm the into signaling the nucleus pathway (Figure 1). This translocatedof AHR has AHRbeen elucidated binds to in its studies specific investigating DNA recognition the toxicity of site, dioxins namely, and polycyclic xenobiotic-responsive aromatic element,pollutants and upregulates [13,27,28]. Upon the ligation transcription by dioxins, of the responsive activated AHR genes, translocates such as from cytochrome the cytoplasm P450 1A1 into the nucleus (Figure 1). This translocated AHR binds to its specific DNA recognition site, namely, (CYP1A1xenobiotic)[13,27‐,responsive28]. CYP1A1 element, is and a member upregulates of athe multigene transcription family of responsive of xenobiotic-metabolizing genes, such as enzymescytochrome [13,27,28 P450]. Besides 1A1 (CYP1A1 its physiological) [13,27,28]. CYP1A1 role is in a themember detoxification of a multigene of family dioxins, of xenobiotic the activity‐ of CYP1A1metabolizing can be deleterious enzymes because[13,27,28]. it Besides generates its physiological mutagenic role metabolites in the detoxification and ROS. of FICZ dioxins, binds the to AHR and upregulatesactivity of theCYP1A1 expression can be ofdeleterious CYP1A1 because in an efficientit generates but mutagenic transient metabolites manner; this and is ROS. because FICZ FICZ is rapidly metabolizedbinds to AHR and by CYP1A1upregulates in the a feedback expression mechanism of CYP1A1 in [25 an,29 efficient]. Extensive but transient studies manner; on the this function is of because FICZ is rapidly metabolized by CYP1A1 in a feedback mechanism [25,29]. Extensive studies AHR using AHR-deficient mice have demonstrated that AHR is responsible for most, if not all, of the on the function of AHR using AHR‐deficient mice have demonstrated that AHR is responsible for toxic effectsmost, caused if not all, by of dioxinsthe toxic [effects30]. caused by dioxins [30]. Figure 1. Activation of AHR. In untreated normal human keratinocytes, AHR (red) is mainly located Figure 1. Activation of AHR. In untreated normal human keratinocytes, AHR (red) is mainly located in in the cytoplasm (A1). Nuclei are stained with 4′,6‐diamidino‐2‐phenylindole (blue, A2). In the 0 the cytoplasmpresence (A1 of ).soybean Nuclei tar are glyteer, stained AHR with is translocated 4 ,6-diamidino-2-phenylindole from the cytoplasm to the (blue, nucleusA2). ( InB1, the red). presence of soybeanNuclei tar are glyteer, stained AHR with 4′ is,6‐ translocateddiamidino‐2‐phenylindole from the cytoplasm (blue, B2). to the nucleus (B1, red). Nuclei are stained with 40,6-diamidino-2-phenylindole (blue, B2). Nutrients 2017, 9, 223 3 of 11 In addition to oxidative stress, recent studies have demonstrated that the AHR system mediates