The Experts below are selected from a list of 2004 Experts worldwide ranked by ideXlab platform
Hongbing Wang - One of the best experts on this subject based on the ideXlab platform.
-
Methadone induces the expression of hepatic drug-metabolizing enzymes through the activation of pregnane X Receptor and Constitutive Androstane Receptor. Drug Metab. Dispos
2020Co-Authors: Antonia H Tolson, Hongbing Wang, Natalie D EddingtonAbstract:Abstract Methadone (MD) is the most established substance abuse pharmacotherapy of choice for the management of heroin dependence. To date, drug-drug interactions involving MD have been characterized asymmetrically among existing reports, which describe how other drugs affect the metabolic or pharmacokinetic profiles of MD, yet limited information is available regarding the potential for MD to influence similar fates of coadministered drugs. Moreover, little to no mechanistic evidence has been explored. Here, we demonstrate that MD induces hepatic drug-metabolizing enzymes (DMEs) through the activation of pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR)
-
human Constitutive Androstane Receptor agonist dl5016 a novel sensitizer for cyclophosphamide based chemotherapies
European Journal of Medicinal Chemistry, 2019Co-Authors: Caitlin Lynch, Bryan Mackowiak, Scott Heyward, Hongbing Wang, Menghang Xia, Dongdong Liang, William D Hedrich, Yue Yin, Fengtian XueAbstract:Abstract The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human Constitutive Androstane Receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC50 value of 0.66 μM and EMAX value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells.
-
dl5050 a selective agonist for the human Constitutive Androstane Receptor
ACS Medicinal Chemistry Letters, 2019Co-Authors: Caitlin Lynch, Menghang Xia, Benjamin Diethelmvarela, Fengtian Xue, Dongdong Liang, Hongbing WangAbstract:The Constitutive Androstane Receptor (CAR) is a xenobiotic sensor governing the transcription of genes involved in drug disposition, energy homeostasis, and cell proliferation. However, currently available human CAR (hCAR) agonists are nonselective, which commonly activate hCAR along with other nuclear Receptors, especially the closely related human pregnane X Receptor (hPXR). Using a well-known hCAR agonist CITCO as a template, we report our efforts in the discovery of a potent and highly selective hCAR agonist. Two of the new compounds of the series, 18 and 19 (DL5050), demonstrated excellent potency and selectivity for hCAR over hPXR. DL5050 preferentially induced the expression of CYP2B6 (target of hCAR) over CYP3A4 (target of hPXR) on both the mRNA and protein levels. The selective hCAR agonist DL5050 represents a valuable tool molecule to further define the biological functions of hCAR, and may also be used as a new lead in the discovery of hCAR agonists for various therapeutic applications.
-
Identification of Modulators That Activate the Constitutive Androstane Receptor From the Tox21 10K Compound Library.
Toxicological sciences : an official journal of the Society of Toxicology, 2018Co-Authors: Caitlin Lynch, Bryan Mackowiak, Ruili Huang, Scott Heyward, Srilatha Sakamuru, Hongbing Wang, Menghang XiaAbstract:The Constitutive Androstane Receptor (CAR; NR1I3) is a nuclear Receptor involved in all phases of drug metabolism and disposition. However, recently it's been implicated in energy metabolism, tumor progression, and cancer therapy as well. It is, therefore, important to identify compounds that induce human CAR (hCAR) activation to predict drug-drug interactions and potential therapeutic usage. In this study, we screen the Tox21 10,000 compound collection to characterize hCAR activators. A potential novel structural cluster of compounds was identified, which included nitazoxanide and tenonitrozole, whereas known structural clusters, such as flavones and prazoles, were also detected. Four compounds, neticonazole, diphenamid, phenothrin, and rimcazole, have been identified as novel hCAR activators, one of which, rimcazole, shows potential selectivity toward hCAR over its sister Receptor, the pregnane X Receptor (PXR). All 4 compounds translocated hCAR from the cytoplasm into the nucleus demonstrating the first step to CAR activation. Profiling these compounds as hCAR activators would enable an estimation of drug-drug interactions, as well as identify prospective therapeutically beneficial drugs.
-
antiproliferation of berberine is mediated by epigenetic modification of Constitutive Androstane Receptor car metabolic pathway in hepatoma cells
Scientific Reports, 2016Co-Authors: Lei Zhang, Hongbing Wang, Xiaojie Miao, Xin Wang, Haihui Pan, Hong Ren, Yongrui Jia, Lan Yuan, Guoliang ZhangAbstract:Constitutive Androstane Receptor (CAR) regulates hepatic xenobiotic and energy metabolism, as well as promotes cell growth and hepatocarcinogenesis. Berberine is an ancient multipotent alkaloid drug which derived from Coptis chinensis plants. Here we report that berberine is able to be cellular uptake and accessible to chromatin in human hepatoma HepG2 cells. Berberine induces more apoptosis, cell cycle arrest, but less ROS production in CAR overexpressed mCAR-HepG2 cells. Moreover, berberine inhibits expressions of CAR and its target genes CYP2B6 and CYP3A4. Furthermore, berberine enhances DNA methylation level in whole genome but reduces that in promoter regions CpG sites of CYP2B6 and CYP3A4 genes under the presence of CAR condition. These results indicated that the antiproliferation of berberine might be mediated by the unique epigenetic modifying mechanism of CAR metabolic pathway, suggesting that berberine is a promising candidate in anticancer adjuvant chemotherapy, due to its distinct pharmacological properties in clinic.
David D Moore - One of the best experts on this subject based on the ideXlab platform.
-
Constitutive Androstane Receptor and hepatitis b virus x protein cooperatively induce β catenin activated liver tumors
bioRxiv, 2020Co-Authors: Jessica Scott, Silvia Liu, Kevin C Klatt, Zhen Sun, Qi Guo, Sandra L Grimm, Cristian Coarfa, Bingning Dong, David D MooreAbstract:Background and AimsThe xenobiotic nuclear Receptor Constitutive Androstane Receptor (CAR) is essential for xenobiotic tumor promotion in mouse models. In these models, {beta}-catenin is genetically activated in approximately 80% of tumors. Chronic Hepatitis B Virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), and {beta}-catenin activation is also frequently activated in HBV-associated HCCs. The goal of this research was to determine whether activation of CAR in a mouse model of chronic HBV infection would result in tumor formation and whether these tumors would display increased {beta}-catenin activation. Approach and ResultsWe treated transgenic mice expressing the HBV X protein (HBx) in hepatocytes with a single dose of the potent CAR agonist TCPOBOP. After 10 months, these mice developed large liver tumors that are characterized by {beta}-catenin nuclear localization and upregulation of {beta}-catenin targets. The {beta}-catenin regulator FoxM1 and the oxidative stress master regulator Nrf2, both of which are CAR gene targets, were also overactivated in tumors. The CAR/HBx tumors share a conserved gene signature with HBV-related human hepatocellular carcinoma. ConclusionsActivation of CAR in the presence of HBx results in tumors with strong {beta}-catenin activation. The mouse model we have described reflects the gene expression patterns seen in human HBV-associated HCC and presents an attractive basis for future studies.
-
Constitutive Androstane Receptor differentially regulates bile acid homeostasis in mouse models of intrahepatic cholestasis
Hepatology Communications, 2019Co-Authors: Kang Ho Kim, Sayeepriyadarshini Anakk, Bingning Dong, Jong Min Choi, Clavia Ruth Wootonkee, Armando Arizpe, Sung Yun Jung, Sean M Hartig, David D MooreAbstract:Bile acid (BA) homeostasis is tightly regulated by multiple transcription factors, including farnesoid X Receptor (FXR) and small heterodimer partner (SHP). We previously reported that loss of the FXR/SHP axis causes severe intrahepatic cholestasis, similar to human progressive familial intrahepatic cholestasis type 5 (PFIC5). In this study, we found that Constitutive Androstane Receptor (CAR) is endogenously activated in Fxr:Shp double knockout (DKO) mice. To test the hypothesis that CAR activation protects DKO mice from further liver damage, we generated Fxr;Shp;Car triple knockout (TKO) mice. In TKO mice, residual adenosine triphosphate (ATP) binding cassette, subfamily B member 11 (ABCB11; alias bile salt export pump [BSEP]) function and fecal BA excretion are completely impaired, resulting in severe hepatic and biliary damage due to excess BA overload. In addition, we discovered that pharmacologic CAR activation has different effects on intrahepatic cholestasis of different etiologies. In DKO mice, CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP; here on TC) treatment attenuated cholestatic liver injury, as expected. However, in the PFIC2 model Bsep knockout (BKO) mice, TC treatment exhibited opposite effects that reflect increased BA accumulation and liver injury. These contrasting results may be linked to differential regulation of systemic cholesterol homeostasis in DKO and BKO livers. TC treatment selectively up-regulated hepatic cholesterol levels in BKO mice, supporting de novo BA synthesis. Conclusion: CAR activation in DKO mice is generally protective against cholestatic liver injury in these mice, which model PFIC5, but not in the PFIC2 model BKO mice. Our results emphasize the importance of the genetic and physiologic background when implementing targeted therapies to treat intrahepatic cholestasis.
-
sexually dimorphic regulation and induction of p450s by the Constitutive Androstane Receptor car
Toxicology, 2009Co-Authors: Juan P Hernandez, Wendong Huang, David D Moore, Linda C Mota, William S BaldwinAbstract:The Constitutive Androstane Receptor (CAR) is a xenosensing nuclear Receptor and regulator of cytochrome P450s (CYPs). However, the role of CAR as a basal regulator of CYP expression nor its role in sexually dimorphic responses have been thoroughly studied. We investigated basal regulation and sexually dimorphic regulation and induction by the potent CAR activator TCPOBOP and the moderate CAR activator Nonylphenol (NP). NP is an environmental estrogen and one of the most commonly found environmental toxicants in Europe and the United States. Previous studies have demonstrated that NP induces several CYPs in a sexually dimorphic manner, however the role of CAR in regulating NP-mediated sexually dimorphic P450 expression and induction has not been elucidated. Therefore, wild-type and CAR-null male and female mice were treated with honey as a carrier, NP, or TCPOBOP and CYP expression monitored by QPCR and Western blotting. CAR basally regulates the expression of Cyp2c29, Cyp2b13, and potentially Cyp2b10 as demonstrated by QPCR. Furthermore, we observed a shift in the testosterone 6α/15α-hydroxylase ratio in untreated CAR-null female mice to the male pattern, which indicates an alteration in androgen status and suggests a role for androgens as CAR inverse agonists. Xenobiotic-treatments with NP and TCPOBOP induced Cyp2b10, Cyp2c29, and Cyp3a11 in a CAR-mediated fashion; however NP only induced these CYPs in females and TCPOBOP induced these CYPs in both males and females. Interestingly, Cyp2a4, was only induced in wild-type male mice by TCPOBOP suggesting Cyp2a4 induction is not sensitive to CAR-mediated induction in females. Overall, TCPOBOP and NP show similar CYP induction profiles in females, but widely different profiles in males potentially related to lower sensitivity of males to either indirect or moderate CAR activators such as NP. In summary, CAR regulates the basal and chemically-inducible expression of several sexually dimorphic xenobiotic metabolizing P450s in a manner that varies depending on the ligand.
-
c myc and its target foxm1 are critical downstream effectors of Constitutive Androstane Receptor car mediated direct liver hyperplasia
Hepatology, 2008Co-Authors: William Blancobose, Wendong Huang, David D Moore, Mark J Murphy, Armin Ehninger, Sandra Offner, Christelle Dubey, Andreas TrumppAbstract:In the adult liver, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), an agonist of the Constitutive Androstane Receptor (CAR, NR1I3), produces rapid hepatomegaly in the absence of injury. In this study, we identify c-Myc as a gene induced by CAR and demonstrate that TCPOBOP-induced proliferation of hepatocytes depends on c-Myc function. Moreover, the TCPOBOP-induced cell cycle program (Cdc2, cyclins, MCM proteins, Cdc20, and genes implicated in the spindle assembly checkpoint) is severely impaired in c-Myc mutant livers. Strikingly, many of these genes overlap with a program controlled by the forkhead transcription factor FoxM1, known to control progression through S-phase and mitosis. Indeed, FoxM1 is also induced by TCPOBOP. Moreover, we show that c-Myc binds to the FoxM1 promoter in a TCPOBOP-dependent manner, suggesting a CAR -> c-Myc -> FoxM1 pathway downstream of TCPOBOP. Conclusion: Collectively, this study identifies c-Myc and FoxM1 mediated proliferative programs as key mediators of TCPOBOP-CAR induced direct liver hyperplasia.
-
The Nrf2 Activator Oltipraz Also Activates the Constitutive Androstane Receptor
Drug metabolism and disposition: the biological fate of chemicals, 2008Co-Authors: Wendong Huang, David D Moore, Matthew D. Merrell, Jonathan P. Jackson, Lisa M. Augustine, Craig D. Fisher, Angela L. Slitt, Jonathan M. Maher, Youcai Zhang, Curtis D. KlaassenAbstract:Oltipraz (OPZ) is a well known inducer of NAD(P)H:quinone oxidoreductase (NQO1) along with other enzymes that comprise the nuclear factor E2-related factor 2 (Nrf2) battery of detoxification genes. However, OPZ treatment also induces expression of CYP2B, a gene regulated by the Constitutive Androstane Receptor (CAR). Therefore, this study was designed to determine whether OPZ induces gene expression in the mouse liver through activation of CAR in addition to Nrf2. OPZ increased the mRNA expression of both Cyp2b10 and Nqo1 in C57BL/6 mouse livers. As expected, in livers from Nrf2-/- mice, OPZ induction of Nqo1 was reduced, indicating Nqo1 induction is dependent on Nrf2 activation, whereas Cyp2b10 induction was unchanged. The robust induction of Cyp2b10 by OPZ in wild-type mice was completely absent in CAR-/- mice, revealing a CAR-dependent induction by OPZ. OPZ also induced transcription of the human CYP2B6 promoter-reporter containing the phenobarbital (PB) responsive element in mouse liver using an in vivo transcription assay. Additionally, OPZ induced in vivo nuclear accumulation of CAR at 3 h but, as with PB, was unable to reverse androstanol repression of mouse CAR Constitutive activity in transiently transfected HepG2 cells. In summary, OPZ induces expression of Cyp2b10 and Nqo1 via the activation of CAR and Nrf2, respectively.
Wen Xie - One of the best experts on this subject based on the ideXlab platform.
-
Gadd45b is required in part for the anti-obesity effect of Constitutive Androstane Receptor (CAR).
Acta pharmaceutica Sinica. B, 2020Co-Authors: Xinran Cai, Ye Feng, Wen XieAbstract:Abstract Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic Receptors to treat metabolic diseases. Activation of Constitutive Androstane Receptor (CAR), a xenobiotic-sensing nuclear Receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation.
-
activation of Constitutive Androstane Receptor ameliorates renal ischemia reperfusion induced kidney and liver injury
Molecular Pharmacology, 2018Co-Authors: Youjin Choi, Songrong Ren, Dong Zhou, Anne Caroline S Barbosa, Yongdong Niu, Xiudong Guan, Thomas D Nolin, Youhua Liu, Wen XieAbstract:Acute kidney injury (AKI) is associate with high mortality. Despite evidence of AKI-induced distant organ injury, a relationship between AKI and liver injury has not been clearly established. The goal of this study is to investigate whether renal ischemia-reperfusion (IR) can affect liver pathophysiology. We showed that renal IR in mice induced fatty liver and compromised liver function through the downregulation of Constitutive Androstane Receptor (CAR; -90.4%) and inhibition of hepatic very-low-density lipoprotein triglyceride (VLDL-TG) secretion (-28.4%). Treatment of mice with the CAR agonist 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) prevented the development of AKI-induced fatty liver and liver injury, which was associated with the attenuation of AKI-induced inhibition of VLDL-TG secretion. The hepatoprotective effect of TCPOBOP was abolished in CAR-/- mice. Interestingly, alleviation of fatty liver by TCPOBOP also improved the kidney function, whereas CAR ablation sensitized mice to AKI-induced kidney injury and lethality. The serum concentrations of interleukin-6 (IL-6) were elevated by 27-fold after renal IR, but were normalized in TCPOBOP-treated AKI mice, suggesting that the increased release of IL-6 from the kidney may have mediated the AKI responsive liver injury. Taken together, our results revealed an interesting kidney-liver organ cross-talk in response to AKI. Given the importance of CAR in the pathogenesis of renal IR-induced fatty liver and impaired kidney function, fatty liver can be considered as an important risk factor for kidney injury, and a timely management of hepatic steatosis by CAR activation may help to restore kidney function in patients with AKI or kidney transplant.
-
pregnane x Receptor and Constitutive Androstane Receptor at the crossroads of drug metabolism and energy metabolism
Drug Metabolism and Disposition, 2010Co-Authors: Jie Gao, Wen XieAbstract:The pregnane X Receptor (PXR) and the Constitutive Androstane Receptor (CAR) are two closely related and liver-enriched nuclear hormone Receptors originally defined as xenobiotic Receptors. PXR and CAR regulate the transcription of drug-metabolizing enzymes and transporters, which are essential in protecting our bodies from the accumulation of harmful chemicals. An increasing body of evidence suggests that PXR and CAR also have an endobiotic function that impacts energy homeostasis through the regulation of glucose and lipids metabolism. Of note and in contrast, disruptions of energy homeostasis, such as those observed in obesity and diabetes, also have a major impact on drug metabolism. This review will focus on recent progress in our understanding of the integral role of PXR and CAR in drug metabolism and energy homeostasis.
-
the Constitutive Androstane Receptor is an anti obesity nuclear Receptor that improves insulin sensitivity
Journal of Biological Chemistry, 2009Co-Authors: Jie Gao, Yonggong Zhai, Taira Wada, Wen XieAbstract:Obesity and type 2 diabetes are related metabolic disorders of high prevalence. The Constitutive Androstane Receptor (CAR) was initially characterized as a xenobiotic Receptor regulating the responses of mammals to xenotoxicants. In this study, we have uncovered an unexpected role of CAR in preventing obesity and alleviating type 2 diabetes. Using a high fat diet (HFD)-induced obesity model, we showed that treatment of wild type mice with the CAR agonist 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) efficiently prevented obesity from happening or reversed preinduced obesity. Treatment with TCPOBOP improved insulin sensitivity in both the HFD-induced type 2 diabetic model and the ob/ob mice. In contrast, CAR null mice maintained on a chow diet showed spontaneous insulin insensitivity, which cannot be relieved by TOPOBOP treatment. The hepatic steatosis in HFD-treated mice and ob/ob mice was markedly reduced by the TCPOBOP treatment. The metabolic benefits of CAR activation may have resulted from the combined effect of inhibition of lipogenesis, very low density lipoprotein secretion and export of triglycerides, and gluconeogenesis as well as increases in brown adipose tissue energy expenditure and peripheral fat mobilization. Moreover, the skeletal muscle of CAR-activated mice showed a decreased incomplete oxidation, despite having a lower expression level of peroxisome proliferator-activated Receptor α and its target genes involved in fatty acid oxidation. In summary, our results have revealed an important metabolic function of CAR and may establish this “xenobiotic Receptor” as a novel therapeutic target for the prevention and treatment of obesity and type 2 diabetes.
-
international union of pharmacology lxii the nr1h and nr1i Receptors Constitutive Androstane Receptor pregnene x Receptor farnesoid x Receptor α farnesoid x Receptor β liver x Receptor α liver x Receptor β and vitamin d Receptor
Pharmacological Reviews, 2006Co-Authors: David D Moore, Wen Xie, Shigeaki Kato, David J Mangelsdorf, Daniel R Schmidt, Rui Xiao, Steven A KliewerAbstract:The nuclear Receptors of the NR1H and NR1I subgroups include the Constitutive Androstane Receptor, pregnane X Receptor, farnesoid X Receptors, liver X Receptors, and vitamin D Receptor. The newly emerging functions of these related Receptors are under the control of metabolic pathways, including metabolism of xenobiotics, bile acids, cholesterol, and calcium. This review summarizes results of structural, pharmacologic, and genetic studies of these Receptors.
Paavo Honkakoski - One of the best experts on this subject based on the ideXlab platform.
-
Functional Characterization of a Novel Variant of the Constitutive Androstane Receptor (CAR, NR1I3)
Nuclear Receptor Research, 2018Co-Authors: Viktoria Prantner, Jenni Küblbeck, Ferdinand Molnár, Yuval Cinnamon, Paavo HonkakoskiAbstract:The nuclear Receptor Constitutive Androstane Receptor (CAR; NR1I3) controls the inducible expression of many enzymes and transporters involved in drug metabolism and transport, energy metabolism and toxicity. Single nucleotide variants of CAR are quite rare and usually associated with changes in pharmacokinetics of therapeutic drugs. Recently, a non-synonymous variant (F243S in the wild-type CAR) has been linked to the Kleefstra syndrome (MIM 610253) affecting neurological development. We identified another, previously unknown CAR variant (I281T) in a patient suffering from Kleefstra-like symptoms. Detailed reporter gene assays and molecular modelling indicated that the I281T mutation decreases the ability of CAR to recruit co-activators, likely by interfering with the assembly of functional CAR/retinoid X Receptor (RXR) heterodimers. Although the I281T variant does not seem to cause the features of the patient, the present study adds to our knowledge about CAR function.
-
insights into ligand elicited activation of human Constitutive Androstane Receptor based on novel agonists and three dimensional quantitative structure activity relationship
Journal of Medicinal Chemistry, 2008Co-Authors: Johanna Jyrkkärinne, And Antti Poso, Björn Windshügel, Jenni Küblbeck, Wolfgang Sippl, Toni Ronkko, Anu J Tervo, Maija Lahtelakakkonen, Paavo HonkakoskiAbstract:The human Constitutive Androstane Receptor (CAR, NR1I3) is an important regulator of xenobiotic metabolism and other physiological processes. So far, only few CAR agonists are known and no explicit mechanism has been proposed for their action. Thus, we aimed to generate a 3D QSAR model that could explain the molecular determinants of CAR agonist action. To obtain a sufficient number of agonists that cover a wide range of activity, we applied a virtual screening approach using both structure- and ligand-based methods. We identified 27 novel human CAR agonists on which a 3D QSAR model was generated. The model, complemented by coregulator recruitment and mutagenesis results, suggests a potential activation mechanism for human CAR and may serve to predict potential activation of CAR for compounds emerging from drug development projects or for chemicals undergoing toxicological risk assessment.
-
Discovery of substituted sulfonamides and thiazolidin-4-one derivatives as agonists of human Constitutive Androstane Receptor.
Biochemical pharmacology, 2008Co-Authors: Jenni Küblbeck, Johanna Jyrkkärinne, And Antti Poso, Paavo Honkakoski, Miia Turpeinen, Wolfgang Sippl, Björn WindshügelAbstract:The Constitutive Androstane Receptor (CAR; NR1I3) is a nuclear Receptor responsible for the recognition of potentially toxic endo- and exogenous compounds whose elimination from the body is accelerated by the CAR-mediated inducible expression of metabolizing enzymes and transporters. Despite the importance of CAR, few human agonists are known so far. Following a sequential virtual screening procedure using a 3D pharmacophore and molecular docking approach, we identified 17 novel agonists that could activate human CAR in vitro and enhance its association with the nuclear Receptor co-activator SRC1. Selected agonists also increased the expression of the human CAR target CYP2B6 mRNA in primary hepatocytes. Composed of substituted sulfonamides and thiazolidin-4-one derivatives, these agonists represent two novel chemotypes capable of human CAR activation, thus broadening the agonist spectrum of CAR.
-
Amino acids important for ligand specificity of the human Constitutive Androstane Receptor.
The Journal of biological chemistry, 2004Co-Authors: Johanna Jyrkkärinne, Janne Mäkinen, And Antti Poso, Björn Windshügel, Wolfgang Sippl, Markku Ylisirniö, Mikael Peräkylä, Mikael Peräkylä, Paavo HonkakoskiAbstract:Abstract The human Constitutive Androstane Receptor (CAR, NR1I3) is an important ligand-activated regulator of oxidative and conjugative enzymes and transport proteins. Because of the lack of a crystal structure of the ligand-binding domain (LBD), wide species differences in ligand specificity and the scarcity of well characterized ligands, the factors that determine CAR ligand specificity are not clear. To address this issue, we developed highly defined homology models of human CAR LBD to identify residues lining the ligand-binding pocket and to perform molecular dynamics simulations with known human CAR modulators. The roles of 22 LBD residues for basal activity, ligand selectivity, and interactions with co-regulators were studied using site-directed mutagenesis, mammalian co-transfection, and yeast two-hybrid assays. These studies identified several amino acids within helices 3 (Asn165), 5 (Val199), 11 (Tyr326, Ile330, and Gln331), and 12 (Leu343 and Ile346) that contribute to the high basal activity of human CAR. Unique residues within helices 3 (Ile164 and Asn165), 5 (Cys202 and His203), and 7 (Phe234 and Phe238) were found control the selectivity for CAR activators and inhibitors. A single residue in helix 7 (Phe243) appears to explain the human/mouse species difference in response of CAR to 17α-ethynyl-3,17β-estradiol.
-
Dual action of oestrogens on the mouse Constitutive Androstane Receptor
Biochemical Journal, 2003Co-Authors: Mika Reinisalo, Johanna Jyrkkärinne, Janne Mäkinen, Kaisa Niemi, Hinfan Chung, Pirkko Viitala, Olavi Pelkonen, Paavo HonkakoskiAbstract:mCAR (mouse Constitutive Androstane Receptor; NR1I3) controls the expression of cytochrome P450 as well as other enzymes involved in drug and steroid metabolism. The high basal activity of mCAR can be modulated by inhibitory steroids related to androstenol and by activating xenobiotic chemicals such as 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene and chlorpromazine. The ability of oestrogens and some other xenobiotics to activate mCAR is not clear. In the present study, co-transfection assays in HEK-293 cells indicated that oestrogens varied in their efficacy to activate mCAR, depending on variation at the steroid D-ring and position of hydroxy groups. In general, oestrogens were weaker activators of mCAR than 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene and chlorpromazine. Also, the induction of CYP2B10 mRNA by oestrogens was less pronounced in mouse primary hepatocytes. Yeast two-hybrid assays indicated that, unlike androstenol and the established activators, oestrogens attracted both nuclear Receptor co-repressors and co-activators to the mCAR ligand-binding domain, thus limiting the extent of mCAR activation. This novel dual action is not limited to oestrogens, but is shared by some xenobiotic CYP2B inducers such as clotrimazole and methoxychlor. These findings offer an alternative explanation for the recently suggested nuclear activation step of mCAR.
Midori Yoshida - One of the best experts on this subject based on the ideXlab platform.
-
Essential role of Constitutive Androstane Receptor in Ginkgo biloba extract induced liver hypertrophy and hepatocarcinogenesis.
Food and Chemical Toxicology, 2015Co-Authors: Jun Maeda, Kaoru Inoue, Miwa Takahashi, Yukio Kodama, Ryohei Ichimura, Naoaki Saito, Midori YoshidaAbstract:Ginkgo biloba extract (GBE) is commonly used as a herbal supplement. The National Toxicology Program (NTP) study of GBE reported clear evidence of hepatocarcinogenicity in mice. To clarify the mode of action (MOA) for hepatocarcinogenesis by GBE, we investigated the involvement of the Constitutive Androstane Receptor (CAR) in hepatocarcinogenesis induced by GBE using CAR-knockout (CARKO) and wild type (WT) mice. We used the same lot of GBE that was used for the NTP study. In 1-week GBE dietary treatment, hepatocellular DNA replication was increased in WT mice but not in CARKO mice. In 4- or 13-week treatment, greater hepatic Cyp2b10 induction and hepatocellular hypertrophy were observed in WT mice, whereas these effects of GBE were much smaller in CARKO mice. In a two-stage hepatocarcinogenesis model initiated by diethylnitrosamine, 27-week treatment with GBE resulted in an increase of eosinophilic altered foci and adenomas in WT mice. By contrast, foci and adenomas were clearly less evident in CARKO mice. These results indicate that GBE-induced hepatocarcinogenesis is mainly CAR-mediated. Since CAR-mediated MOA for hepatocarcinogenesis in rodents is considered to be qualitatively implausible for humans, our findings would be helpful to evaluate the carcinogenic characterization of GBE to humans.
-
Involvement of Constitutive Androstane Receptor in liver hypertrophy and liver tumor development induced by triazole fungicides.
Food and Chemical Toxicology, 2015Co-Authors: Kei Tamura, Kaoru Inoue, Miwa Takahashi, Saori Matsuo, Kaoru Irie, Yukio Kodama, Shogo Ozawa, Toshie Gamo, Midori YoshidaAbstract:We clarified the involvement of Constitutive Androstane Receptor (CAR) in triazole-induced liver hypertrophy and tumorigenesis using CAR-knockout (CARKO) mice. Seven-week-old male CARKO and wild-type (WT) mice were treated with 200 ppm cyproconazole (Cypro), 1500 ppm tebuconazole (Teb), or 200 ppm fluconazole (Flu) in the diet for 27 weeks after initiation by diethylnitrosamine (DEN). At weeks 4 (without DEN) and 13 (with DEN), WT mice in all treatment groups and CARKO mice in Teb group revealed liver hypertrophy with mainly Cyp2b10 and following Cyp3a11 inductions in the liver. Teb also induced Cyp4a10 in both genotypes. Cypro induced slight and duration-dependent liver hypertrophy in CARKO mice. At week 27, Cypro and Teb significantly increased eosinophilic altered foci and/or adenomas in WT mice. These proliferating lesions were clearly reduced in CARKO mice administered both compounds. The eosinophilic adenomas caused by Flu decreased in CARKO mice. The present study indicates that CAR is the main mediator of liver hypertrophy induced by Cypro and Flu, but not Teb. In contrast, CAR played a crucial role in liver tumor development induced by all three triazoles.
-
dose response involvement of Constitutive Androstane Receptor in mouse liver hypertrophy induced by triazole fungicides
Toxicology Letters, 2013Co-Authors: Kei Tamura, Kaoru Inoue, Miwa Takahashi, Saori Matsuo, Kaoru Irie, Yukio Kodama, Shogo Ozawa, Akiyoshi Nishikawa, Midori YoshidaAbstract:To clarify the dose-response relationship between Constitutive Androstane Receptor (CAR) activity and induction of cytochrome P450 2B (CYP2B) expression and hypertrophy by triazole fungicides in mouse liver, three dose levels of cyproconazole (Cypro), tebuconazole (Teb), fluconazole (Flu), and phenobarbital (PB), a typical CYP2B inducer, were administrated in diet to male wild-type (WT) and CAR-knockout (CARKO) mice for one week. In WT mice, all compounds dose-dependently induced liver weight increases and hepatocellular hypertrophy accompanied by CYP2B expression. In CARKO mice, these effects were not induced by PB, while Cypro or Flu induced these effects only at the highest dose. Dose-dependent liver hypertrophy was detected in CARKO mice treated with Teb, but at the lowest dose the intensity was weakened compared to WT mice. The present results indicate that Cypro and Flu mainly induced CAR-mediated liver hypertrophy, while Teb slightly involved CAR. The involvement of CAR in triazole-induced liver hypertrophy was dose-responsive. In addition, all three triazoles have non-CAR-mediated liver hypertrophy pathways, indicating that the hypertrophy induced by these triazoles differs from that of PB.