Journal of Steroid Biochemistry & Molecular Biology 147 (2015) 24–30

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Review

Cytochrome P450 1 family and cancers Ryeo-Eun Go, Kyung-A Hwang, Kyung-Chul Choi * Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763,Republic of Korea

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 September 2014 Received in revised form 28 October 2014 Accepted 3 November 2014 Available online 6 November 2014

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor that dimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT). This complex binds to xenobiotics response element (XREs), and then starts the expressions of downstream genes including cytochrome P450 (CYP) 1 family members: CYP1A1, CYP1A2 and CYP1B1. Role of CYP1 family is involved in the metabolism of endogenous hormones, xenobiotics and drug. The expression of CYP1 family is regulated by estradiol (E2) or xenobiotics in diverse cancers. In breast cancers expressing estrogen receptors (ERs), level of CYP1B1 is increased by E2 and reversed by an estrogen receptor antagonist, ICI 182,780 or 4-hydrotamoxifen, which indicates that the expression of CYP1 family in downstream region of AhR is regulated by an activation of ERa. In metabolic pathways, E2 is converted into 4-hydroxyestradiol by CYP1B1, which can be converted into mainly estradiol-3,4-quinone, a potential carcinogen, by peroxidase. Increased expression of CYP1 family indicates the possibility of carcinogenesis by exposure of xenobiotics in endometrial and ovarian cancers. Apart from roles of CYP1 family in relation with ER pathway, CYP1 family is over-expressed in ER independent cancers. CYP1A1 exhibits hydroxylase activity in oxidation of arachidonic acid, which has been transformed to 12(R)-hydrxyeicosatetraenoic (HETEs), a potent activator of AhR activity. On the basis of results, phytoestrogens and dexamethasone are provided as cancer therapy regulating the expression of CYP1 family. Thus, this review focuses on the role(s) of CYP1 family in ER-dependent or ER-independent cancers and the potential for cancer therapy to target CYP1 family in these cancers. ã 2014 Elsevier Ltd. All rights reserved.

Keywords: Cytochrome P450 1 family Aryl hydrocarbon receptor Estrogen receptor

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The relevance of CYP1 family in ER-dependent cancers . . . . . . . . . . . . . . . Metabolism of estrogen by CYP1 family . . . . . . . . . . . . . . . . . . . . . . 2.1. Effect of ERa on AhR dependent expression of CYP1 family . . . . . . 2.2. Effect of CYP1 family gene expression in ER positive-breast cancer 2.3. Effect of CYP1 family gene expression in other ER-positive cancers 2.4. The relevance of CYP1 family in ER-independent cancers . . . . . . . . . . . . . . Effect of CYP1 family in liver cancer . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Effect of CYP1 family in bladder cancer . . . . . . . . . . . . . . . . . . . . . . 3.2. Cancer therapy regulating CYP1 family expression . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: 3MC, 3-methylcholanthrene; 50 - AMPK, 50 AMP-activated protein kinase; AhR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; BaP, benzo(a) pyrene; CHIP assay, chromatin immunoprecipitation; CYP1A1, cytochrome P450, family 1, subfamily A, polypeptide 1; CYP1A2, cytochrome P450, family 1, subfamily A, polypeptide 2; CYP1B1, cytochrome P450, family 1, subfamily B, polypeptide 1; CYP 450P 1 family, cytochrome P450 1 family; DEX, dexamethasone; DPAA, diphenylarsinic acid; E2, 17b-estradiol; ER, estrogen receptor; ERE, estrogen response elements; EROD, ethoxyresorfin-?-deethylase; G1 phase, growth 1/cap 1 phase, the first of four phases of the cell cycle; GR, glucocorticoid receptor; HAHs, halogenated aromatic hydrocarbons; HETEs, hydroxyeicosatetraenoics; HOSE, human ovarian surface epitherium; ICI 182,780, ERa antagonist; KAE, kaempferol, 3,40 ,5,7-tetrahydroxyflavone; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; PAHs, polycyclic aromatic hydrocarbons; RES, resveratrol, trans-3,40 ,5-trihydroxystilbene; RU456, glucocorticoid receptor antagonist; S phase, the part of the cell cycle in which DNA is replicated; TCDD, 2,3,7,8-tetrachlorodibenzo-r-dioxin; XREs, xenobiotics response element. * Corresponding author. Tel.: +82 43 261 3664; fax: +82 43 267 3150. E-mail address: [email protected] (K.-C. Choi). http://dx.doi.org/10.1016/j.jsbmb.2014.11.003 0960-0760/ ã 2014 Elsevier Ltd. All rights reserved.

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Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

1. Introduction A role of cytochrome P450 (CYP) superfamily is involved in transporting electrons from nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) to adrenodoxin in microsome [1,2]. CYP superfamily consists of 57 genes and is divided into 18 families in human for the synthesis of endogenous hormones and the metabolism of xenobiotic substrates [3–5]. CYP 1 family, a member of the CYP superfamily, includes three proteins: CYP1A1, CYP1A2, and CYP1B1 [4,6]. In human, CYP1A1 is found mainly in extrahepatic tissues: pancreas, thymus, uterus, and small intestine, and participates in the metabolism of a vast number of xenobiotics. CYP1B1 is abundantly expressed in extrahepatic tissues such as the prostate, breast, and uterus, and frequently overexpressed in tumor tissue [7,8]. The amino acid sequence of CYP1B1 is highly conserved among humans, rats, and mice (80% identity) and is similar to that of CYP1A1 (40%). The transcription of CYP 1 family is regulated through aryl hydrocarbon receptor (AhR), which is responsible for regulating the activity of CYP 1 family as a ligand-activated transcription factor [9]. Xenobiotics such as 2,3,7,8-tetrachlorodibenzo-r-dioxin (TCDD), an halogenated aromatic hydrocarbons (HAHs), benzo(a) pyrene (BaP), and polycyclic aromatic hydrocarbons (PAHs), are AhR binding ligands [9,10]. In case of binding with these ligands (xenobiotics), AhR regulates the transcriptional activation of CYP1A1, CYP1B1, and CYP1A2 that are involved in the bioactivation of procarcinogenic compounds to carcinogenic derivatives and drug metabolism [11]. The biological actions mediated by AhR are the result of multi-step process of signal transduction [12]. In this process, ligand binded AhR translocates from the cytoplasm into the nucleus and forms a complex by dimerizing with aryl hydrocarbon receptor nuclear translocator (ARNT). This complex then binds to xenobiotics response elements (XREs) and modulates the expression of various genes including CYP 1 family members; CYP1A1 and CYP1B1, as seen from Fig. 1 [13–15]. Consequently, expression levels of CYP1A1 and CYP1B1 may reflect HAHs or PAH-induced immunotoxicity, oxidative stress, and activation of environmental carcinogens [16]. Especially, the roles of AhR signal transduction

process and CYP1 family in the metabolism of xenobiotics have been subjects of study in respect of the bioactivation of procarcinogenic compounds to carcinogens responsible for pathogenesis of cancer. According to World Health Organization (February 2014, Retrieved 10 June 2014, http://www.who.int/mediacentre/factsheets/fs297/en/), cancer is a group of diseases resulting from the overgrowth of cells with the potential to invade or divide into other parts of the body. Cancer is a main cause of death worldwide, amounting to 8.2 million deaths in 2012 according to IARC (http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx). The most common types of cancer in men are lung, prostate, colon and liver cancer, and in women, breast, colon, uterus, lung and ovary cancer. The most common types of cancers, which are the main cause of death in humans, are lung, liver, stomach, colon, and breast cancers (2012, IARC). Diverse causes of cancer have been known to include the exposure to chemicals or physical agents involving tobacco, radiation, overweight or underweight, environmental pollutants, and some hormones [17]. Among hormones, estrogens that are primary female sex hormones have been reported to be linked to the pathogenesis of several cancers in the reproductive organs such as breast, ovary, and endometrium [18–22]. These organs express the receptors of estrogens (ERs) and the actions of estrogen mediated by ERs closely affect cancer formation and growth [18,19]. In this review, we discuss the roles of CYP1 family in connection with diverse cancers by dividing into ER-dependent and ER-independent signaling pathways and the potential for cancer therapy to target CYP1 family. 2. The relevance of CYP1 family in ER-dependent cancers 2.1. Metabolism of estrogen by CYP1 family Estrogens are endogeneous steroid sex hormones including estrone (E1), 17b-estradiol (E2), and estriol (E3). Among these, E2 is the most potent estrogen [23]. Estrogens affect the development and growth of ovaries, adrenal glands, and fat tissues and also influence the development of secondary sexual

Fig. 1. Mechanism of activation of CYP450 family genes by binding of the complex of AhR and ARNT on XRE. Ligand binded AhR translocates from the cytoplasm into the nucleus and forms a complex by dimerizing with aryl hydrocarbon receptor nuclear translocator (ARNT). This complex then binds to xenobiotics response elements (XREs) and modulates the expression of various genes including CYP1 family members, CYP1A1 and CYP1B1.

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characteristics and the reproductive system. In addition, they not only influence bone growth, protein synthesis, and fat deposition, but are also linked to the pathogenesis of female cancers and diseases of the reproductive organs including the breast, ovary, and endometrium [24,25]. Estrogen responsive cancers usually express ER to deliver the signals of estrogen [24–27]. For instance, E2 induces the transition of the cell cycle from G1 to the S phase and promotes the growth of cancer cells such as ER–positive MCF7 breast and BG-1 ovarian cancer cells as a result of ER signaling pathway [26,28]. The connection of CYP1 family to these cancers was firstly known through its role in the metabolism of estrogens. According to steroid hormone biosynthesis-reference pathway of Kyoto University Bioinformatics Center (https://en.wikiversity.org/ wiki/Diagram_of_the_pathways_of_human_steroidogenesis), the synthesis of estrogens begins with the synthesis of androstenediol from cholesterol in the ovary. The conversion of androstenediol to testosterone is catalyzed by 17b-hydroxysteroid dehydrogenases, and then the conversion of testosterone into E2 is catalyzed by aromatase. In the metabolism of estrogen, E2 is converted into 4hydroxyestradiol by CYP1B1, which can be converted into 4methoxyestradiol by catechol-O-methyltransferase or mainly estradiol-3,4-quinone by peroxidase [29,30]. Estradiol-3,4-quinone has the carcinogenicity as DNA adducts formation [31]. Taken together, the enzymes of CYP1 family may cause or amplify estrogen responsive cancers by inducing the formation of a carcinogenic metabolite from original estrogen [32]. In these processes, CYP1B1 proteins acts as key players among CYP1 family [33]. 2.2. Effect of ERa on AhR dependent expression of CYP1 family Though the enzymes of CYP1 family exist in most tissues, they especially play important roles that are related with carcinogenesis or cancer proliferation in estrogen responsive or ER expressing organs including breast and ovary. Meanwhile, as the expression of CYP1 family is regulated by AhR, the changes in AhR signaling pathway may cause a break in hormone homeostasis of estrogen in ER expressing organs leading to cancer [29,34–36]. The activity of ethoxyresorfin-?-deethylase (EROD), an enzyme of CYP1 family, is widely used as a biomarker for monitoring the activity of CYP1A1 along with exposure to substances that bind to AhR such as HAHs and PAHs. The activity of EROD induced by CYP1A1 is experimentally measured by the value of the oxidation of 7-ethoxyresorufin to resorufin [37]. EROD activity was increased by treatment of TCDD or E2 in mouse ovarian surface epithelial cells (ID8 cells). Co-treatment of E2 and TCDD caused more increase of EROD activity than each treatment of TCDD or E2 in a dose-dependent manner, but these levels were inhibited by ICI 182,780, an ER antagonist, showing that the inactivation of ER may influence on the expression of CYP1A1 by TCDD via AhR [38]. In addition, the recruitment of AhR or ERa on CYP1A1 enhancer was more increased by the co-treatment of TCDD and E2 than by only E2 or TCDD in Chip assays (chromatin immunoprecipitation) using human ECC-1 endometrial carcinoma cells. ECC-1 cells were treated with E2 or TCDD after became transfected with siRNA of AhR, the expression level of CYP1A1 mRNA was decreased, though the expression level of ERa protein did not change, indicating that the silencing of AhR may also affect the expression of CYP1A1 caused by E2 [39]. These findings collectively suggest that E2 and ERa may be involved in the activation of CYP1A1 induced by AhR. An interaction between ERa and AhR involved in CYP1 family activation is still controversial, because their interaction may vary according to cell culture conditions or species [12,38,40–42].

2.3. Effect of CYP1 family gene expression in ER positive-breast cancer Breast cancer is the common invasive cancer in women and develops from breast tissue. The causal factors of breast cancer are female sex, older age, genetics, higher levels of certain hormones, and obesity [43–45]. The structural modification of estrogen also has relevance to breast cancer. 4-hydroxylation of E2 is confirmed to account for a significant level in breast cancer. Level of 4-hydroxylation in breast cancer is more higher compared with normal breast tissue and this process is conducted by CYP1B1 [46]. Among other different histological types of breast cancer, CYP1B1 is over-expressed in an invasive ductal type. The more a grade of breast cancer increases, the more the expression level of CYP1B1 is increased. In addition, the immune-reactivity for CYP1B1 appears in the breast cancer expressing ER with a chance of about 60% [47]. Therefore, this result indicates that CYP1B1 of CYP1 family has a major role in breast cancer in relation with breaking the homeostasis of estrogen [30,48]. MCF-7 cell line is cells of classic ER-positive and invasive breast ductal carcinoma [49–51]. Because MCF-7 cells have ER, their proliferation is regulated by estrogen [52–54]. In addition, because CYP1B1 proteins in MCF-7 cells appear to be a high level, the regulations on the expression of CYP1 family have been researched with reference to carcinogenesis or cancer treatment. Transcription of CYP1B1 was more induced by treatment of E2 than vehicle in MCF7 cells, but not in ER-negative cancer cells such as MDA-MB-435 [55]. When MCF-7cells that were transfected with luciferase plasmid in 50 -flanking region of CYP1B1 to identify transcriptional level of CYP1B1 were treated with E2, transcriptional activity increased about five-times. But after treated with ER antagonist such as ICI 182,780 or 4-hydrotamoxifen, transcriptional activity was significantly reduced in the presence of E2. These results suggest that transcriptional activation of CYP1B1 is induced by E2 [55]. The transcriptional activation of CYP1B1 was also confirmed by increased expression of resorufin which is formed in an EROD assay using MCF7 cells treated with 1 nM E2 for 10 days [56]. When MCF-7 cells were treated with E2 for a long-time, the expression level of ERa decreased due to the combination ERa and E2. However, by forming more complex of ERa and E2 combination with AhR, downstream gene of AhR including CYP1A1 or CYP1B1 up-regulates compared to control not treated with E2 [14,15,56]. As a result, the upregulation of CYP1 family in ER-positive breast cancer cells was induced by the interaction of ERa in an AhR-induced signal transduction and this overall hypothesis has been summarized in Fig. 2.

2.4. Effect of CYP1 family gene expression in other ER-positive cancers The human female reproductive system contains uterus, fallopian tubes, and ovaries of which development or reproductive cycle is mainly influenced by E2 [23–25]. Endometrial cancer is a type of cancer arousing in the lining of the uterus resulting from excessive estrogen exposure or obesity [57,58]. In the endometrium, it has been known that the expression of CYP1B1 is regulated by estrogen and CYP1B1 protein is strongly found in functional layers susceptible to E2. The association of ERa with the putative estrogen response elements (ERE) on the human CYP1B1 gene promoter is demonstrated in intact cells by CHIP assay [55]. This study suggests that the increased E2 level during menstrual cycle supports the presence of E2-dependent activation pathway of CYP1B1. As a result of the induction of CYP1B1 expression, the synthesis of 4-hydroxyestradiol, which can lead to carcinogenesis by making a free radicals in endometrial adenocarcinoma, was increased [35,59–62]. As an exogenous factor affecting the CYP1 level, the effect of cigaret smoke was studied. BaP, a

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Fig. 2. Proposed mechanisms of AhR-ER crosstalk on the activation of XRE. Complex of AhR-ARNT and AhR agonist may dimerize with an ERa-ER agonist complex, and then activate XRE, leading to the elevated expression levels of CYP450 family: CYP1A1 and CYP1B1.

hydrocarbon in cigaret smoke, induced EROD activity and increased the expression level of CYP1A1 in a dose-dependent manner in PL95-2 endometrial epithelial cells expressing of ERa [63,64]. These results suggest that estrogen metabolism in the endometrium is changed by induction of CYP1 family resulting from exposure of cigaret to smoke [65]. High expression levels of CYP1B1, a downstream gene of AhR, in the ovary is correlated with ovarian tumor [66]. Ovarian cancer is included in the gynecologic neoplasm and it is the leading cause of death; 14,000 cases of death in the diagnosed 23,000 cases [67]. The majority of ovarian cancer is epithelial cancer arising from human ovarian surface epitherium (HOSE), that is caused by dietary or environmental factors such as high levels of meat consumption, excessive caffeine intake, cigaret smoking, and environmental pollutants including TCDD and metabolically activated carcinogens [67–70]. According to previous researches, CYP1B1 is consistently expressed in normal and immortalized HOSE whereas CYP1A1 is weakly expressed or not. However, in ovarian cancer cells (OVCA), CYP1A1 is over-expressed and CYP1B1 is consistently expressed [71]. In mouse ovarian cancer cells treated with TCDD, E1, 2-hydroxyestradiol, and 4-hydroxyestradiol increased EROD activity in a dose-dependent manner. EROD activity induced by E2 is inhibited by ICI182,780, suggesting that enhancement of EROD activity by E2 is mediated by ERa [38]. In addition, the elevated expression of CYP 1 family in reproductive system, i.e., endometrium and ovary, implies the possibility of xenobiotic exposure. 3. The relevance of CYP1 family in ER-independent cancers Apart from the role of CYP1 family related with ER pathway in ER-dependent cancers, CYP1 family also plays an essential part in ER independent cancers and is usually over-expressed in these types of cancer. Because CYP1 family including of CYP1A1 and CYP1B1 catalyzes the oxidation of pro-carcinogens to carcinogenic reactive intermediates, the over-expression of CYP1 family is an important contributor to carcinogenesis [72]. CYP1 family is also in charge of the metabolism of drugs and endogenous compounds to possess the potent biological activities [73]. For example, CYP1A1 exhibits hydroxylase activity in oxidation of arachidonic acid. Arachidonic acid has been transformed into hydroxyeicosatetraenoics (HETEs) including 5-,8-,9-,11-,12-, and 15-HETEs in this process [74–76]. 12(R)-HETE is a potent activator of AhR and possibly involves in inflammatory disease condition of skin [77]. In breast cancer, CYP1A1 regulates cancer cell proliferation and survival via suppression of 50 AMP-activated protein kinase (50 -

AMPK) signal and metastasis via involvement in b-catenin signal [78–80]. As mentioned, CYP1 family affects ER-independent cancers by regulating diverse signaling pathways. 3.1. Effect of CYP1 family in liver cancer As mentioned earlier, CYP1 family not only synthesizes steroid hormone such as estrogen, but also metabolizes xenobiotics such as BaP TCDD, cyprodinil, and diphenylarsinic acid (DPAA). Cyprodinil is a pyrimidinamine-type fungicide with an inhibitory effect on the biosynthesis of methionine and other thionic amino acids of fungi and used worldwide in agriculture. Grapes and apples in table are the major contributors of cyprodinil exposure in children. After oral administration, cyprodinil was rapidly excreted in rat urine in the form of dihydroxy metabolite [81–83]. However, cyprodinil accumulated in liver may induce CYP1 family activation and carcinogenesis. In the mouse hepatoma cell line, Hepa-1c1c7, CYP1A1 promoter was activated and the expression of CYP1A1 protein was increased by cyprodinil in time- and dose-dependent manners. Similar to BaP, cyprodinil was shown to activate the CYP1A1 by facilitating the translocation of AhR into the nucleus. Therefore, when Hepa-1c1c7 cells lacked ARNT and AhR, CYP1A1 was not induced by cyprodinil, indicating that cyprodinil has a potential carcinogenicity by inducing the transcriptional activity of CYP1A1 via AhR pathway [84]. DPAA, an inorganic arsenical compound, is used in chemical warfare as one of respiratory irritants [85–88]. Exposure of inorganic arsenic causes cancer in lung, urinary bladder, and skin [89]. Its accumulation in liver and kidney of rats has been demonstrated to induce carcinogenesis in the process of metabolism [90]. DPAA significantly induced the mRNA expression of CYP1B1 among other CYP proteins in livers and the number and areas of preneoplastic lesion with GST-P-positive foci in rat livers were significantly increased in the treatment of 20 ppm DPAA in 8 weeks. This result suggests that CYP1B1 might be responsible for DPPA metabolism leading to elevated hepatocarcinogenesis in liver [91–93]. 3.2. Effect of CYP1 family in bladder cancer In Korea, the 5-year survival rate for bladder cancer is 75.4% and approximately 3500 cases of bladder cancer were newly diagnosed in men in 2011 [94]. Bladder cancer is localized above the basement membrane of bladder and becomes invasive carcinomas when the tumor penetrates the transitional epithelium [95]. Also in bladder cancer, the elevated expression level of CYP genes was observed as a result of the processes involving the activation of

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AhR. CYP1 family, as key regulators of metabolism of xenobiotics or endogenous hormones, is synthesized by the translocation of inducer-receptor complex into the nucleus [96–99]. CYP1 family reactions are mixed-function oxidations and commonly occur in an anabolic or/and catabolic reaction [100]. CYP1 family induced the formation of reactive arylamine: oxidation of any arylamine into N-hydroxylated product in liver. N-hydroxylated product combined with hydrogen atoms causes urinary bladder toxicity [101]. For this reason, the expression level of CYP1 family can be used as a biomarker for the exposure of xenobiotics in bladder cancer. Transcription levels of CYP1A1 and CYP1B1 in bladder cancer were significantly increased more than in normal bladder cells. Especially, the transcription level of CYP1A1 varied significantly depending on the stage of tumor. In the linear regression analysis for the relationship of CYP1B1 mRNA with CYP1 total activity in cancer, the expression level of CYP1B1 is proportional to CYP1 total activity [102]. According to other studies on clinical bladder samples, bladder tumor highly expressed CYP1A1, CYP1A2, and CYP1B1 in common compared to normal tissues [103]. In view of the results achieved so far, these studies may suggest an insight of the contribution of CYP1 expression in cancer pathology and a tool of cancer therapy targeting CYP1 family. Therefore, therapeutic candidates able to regulate the expression of CYP1 family will be briefly introduced in the next section. 4. Cancer therapy regulating CYP1 family expression Phytoestrogens, plant-derived estrogenic compounds, have been demonstrated to have anti-CYP1 family activities along with their diverse biological efficacies. Kaempferol (KAE; 3,40 ,5,7-tetrahydroxyflavone) is a flavonoid with a structure distinct from those of other flavonesamongphytoestrogens,andappearstoexertanti-oxidantand anti-neoplastic effects on cancer cells [104]. Resveratrol (RES; trans3,40 ,5-trihydroxystilbene)isanaturalpolyphenoliccompoundknown as a phytoestrogen similar to KAE that has beneficial anti-estrogenic and anti-cancer effects in cases of estrogen-dependent cancers [105]. KAE and RES suppressed TCDD-induced AhR-mediated transcription and reduced mRNA expression levels of CYP1A1 and CYP1B1 in the presence of TCDD in T-47D cells, a human ductal breast epithelial tumor cell line, despite ERa is knocked out [42]. Furthermore, RES (20 mM)appearedto suppresstheexpressionofCYP1A1mRNAupto a vehicle control. Expression levels of CYP1A1, CYP1A2, and CYP1B1 mRNA were clearly decreased by RES compared to TCDD in MCF-7cells.Moreover,CYP1A1andCYP1B1mRNAexpressionsmaybe reducedatvariousconcentrationsofRESinadose-dependentmanner [4,42]. These results indicate that RES and KAE inhibit the enzymatic activities of phase I drug metabolizing enzymes including CYP1A1, CYP1B1, and CYP1A2, regardless of ER-pathway [6,106]. Dexamethasone (DEX) is a member of the glucocorticoid class of steroid drugs, which has anti-inflammatory and immunosuppressant effect. In placental JEG-3 cells, the activation of XRE-luc by 3-methylcholanthrene (3MC) treatment and transcription level of CYP1A1 by TCDD treatment were significantly suppressed by DEX treatment. When treated with RU486, glucocorticoid receptor (GR) antagonist, the transcription level of CYP1A1 and XRE-luc was suppressed. This result suggests the possibility of cancer therapy regulating CYP1A1 expression via GR pathway [107]. 5. Conclusion Xenobiotics such as TCDD or BaP combine with AhR and this complex translocate from the cytoplasm into the nucleus. And then the complex binds to XREs after dimerized with ARNT and modulates the expression of CYP 1 family such as CYP1A1 and CYP1B1. CYP1 family plays an important role in the metabolism of endogenous hormones and xenobiotic substrates. CYP1A1 is found

mainly in extrahepatic tissues of the metabolism of a vast number of xenobiotic, also CYP1B1 is abundantly expressed in extrahepatic tissues and over expressed in tumor tissue. Estrogen is essential hormone in human not only to regulate the development and growth of reproductive system, but also to influence the development of secondary sexual characteristics. The overproduction of estrogen such as E2 or the bioconversion of E2 into carcinogenic metabolites such as estradiol-3,4-quinone or 4-hydroxyestradiol by CYP1B1 may cause the cancer in estrogen dependent organs. In addition, the expression of CYP1 family is closely associated with estrogen signaling pathway. EROD activity is a biomarker for monitoring the activity of CYP1A1 by the exposure of environmental chemical contaminants as HAHs and PAHs. The increased EROD activity by these chemicals is reversed by ER antagonist in estrogen dependent MCF-7 breast cancer cells, suggesting the relationship of AhR signaling pathways via ER pathways in CYP1 family expression. The increased CYP1A1 enzymes induce breast cancer proliferation and survival via suppression of 50 -AMPK and b-catenin signaling. Also in ovary, over-expression of CYP1B1 by the activation of AhR may cause ovarian tumor, through the number of follicles in developmental stages is decreased by knockout of AhR. Regardless of estrogen, CYP1 family is over-expressed in ER independent cancers such liver and bladder cancer. In these organs, CYP1A1 induces the oxidation of arachidonic acid and transforms it into 12(R)-HETE, a potent activator of AhR activity, leading to inflammatory disease and cancer. The liver has a wide range of functions including detoxification, protein synthesis and production of biochemicals. Because the metabolism of xenobiotics such as BaP, TCDD, cyprodinil, and DPAA primarily occurs in liver, the over-expression of CYP1 family resulted from this metabolism has more fatal effects. Liver exposed to DPAA is significantly divided into the preneoplastic lesions with GST-P-positive foci in rats. In the process of arylamine activation by CYP1 family, the atoms of hydrogen produced cause urinary bladder toxicity and increase the possibility of carcinogenesis. Actually, bladder tumor significantly expresses CYP1A1, CYP1A2 and CYP1B1 in clinical samples compared to normal tissue. From the results of these studies, some researchers suggest that CYP1 family may be a target for cancer therapy. RES and KAE are phytoestrogens that have anti-cancer effects in cases of estrogen-dependent cancers. Moreover, these chemicals have the beneficial effects on suppressing the expression of CYP1 family. They reduced the mRNA expressions of CYP1A1 and CYP1B1 in breast cancer cells exposed to TCDD. In addition, DEX reduced the transcription level of CYP1A1 induced by TCDD or 3MC. In conclusion, the genes in CYP1 family including CYP1A1 and CYP1B1 may be critical makers in diverse types of cancers because they are over-expressed to induce the carcinogenicity in the metabolism of exogenous xenobiotics or endogenous hormones. It can be hypothesized the CYP1A1 may be the possibility of cancer therapy via its regulation. Although many studies have been done to identify the role of CYP1 family in diverse cancer models, more detailed studies should be carried out to clarify its underlying mechanisms for clinical use. Conflict of interest None of the authors have any conflicts of interest to declare. Acknowledgements This work was supported by National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) of Korea Government (2013R1A1A2059092).

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