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Pregnane X receptor and constitutive androstane receptor modulate differently CYp3A-mediated metabolism in earlyand late-stage cholestasis

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World Journal of Gastroenterology 2017年第42期23卷 7519-7530页

作者： Daniela Gabbia Arianna Dalla Pozza Laura Albertoni Roberta Lazzari Giorgia Zigiotto Maria Carrara Vincenzo Baldo Tatjana Baldovin Annarosa Floreani Sara De Martin Department of Pharmaceutical and Pharmacological Sciences University of Padova Department of Medicine General Pathology and Cytopathology UnitUniversity of Padova Department of Cardiac Thoracicand Vascular SciencesHygiene and Public Health UnitUniversity of Padova Department of Surgery Oncology and GastroenterologyUniversity of Padova

AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of Pregnane X receptor(PxR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PxR, CAR, CYP3 A1 and CYP3 A2 were assessed by means of q RT-PCR and Western blot, respectively. Alterations in CYP3 A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3 A enzymes.RESULTS The m RNA and protein expression of CYP3 A1 increased significantly in mild cholestasis(P xpression of CYP3 A2 didn't change in mild cholestasis, whereas the expression and activity of both CYP3 A1 and CYP3 A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PxR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently, probably as consequence of the different activation of PxR and CAR.CONCLUSION Early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently. PxR and CAR might be targeted therapeutically to promote CYP3 Amediated liver detoxification.

关键词： Cholestasis CYP3A Drug metabolism Pregnane X receptor Constitutive androstane receptor

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Pregnane X receptor： a double-edged sword

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Chinese Medical Journal 2009年第11期122卷 1333-1341页

作者： FANG Dao-kui ZHANG Jian-qing Persistent Organic Pollutant Laboratory Shenzhen Center for Disease Control and Prevention Shenzhen Guangdong 518020 China

During the last decade, much progress has been made in exploring the mechanisms of alterations elicited by foreign compounds in xeno- and endobiotic metabolism regulated by the human nuclear Pregnane X receptor （PxR）. PxR, identified as a human nuclear receptor in 1998 and generally regarded as a sensor activated by exogenous and endogenous chemicals, regulates a large number of enzymes and transporters involved in the response of mammals to their chemical environment.

关键词： Pregnane X receptor protein structure function

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Interaction of Hepatitis B Virus x Protein with the Pregnane X receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis

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Journal of Clinical and Translational Hepatology 2021年第4期9卷 466-476页

作者： Yongdong Niu Shaohua Fan Qin Luo Liming Chen Danmei Huang Wenjun Chang Wenxin Qin Ganggang Shi Department of Pharmacology Shantou University Medical CollegeShantouGuangdongChina Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province School of Life ScienceJiangsu Normal UniversityXuzhouJiangsuChina State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Department of Oncology First Affiliated Hospital of Shantou University Medical CollegeShantouGuangdongChina Department of Environmental Hygiene Second Military Medical UniversityShanghaiChina

Background and Aims:Hepatitis B virus(HBV)infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics,by unknown mechanisms,in the generation of hepatocellular carcinoma.The Pregnane X receptor(PxR)is a key regulator of the body’s defense against xenobiotics,including xenobiotic carcinogens and clinical drugs.In this study,we aimed to investigate the molecular mechanisms of HBV x protein(HBx)-PxR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.Methods:The expression profile of PxR-cytochrome p4503A4(CYP3A4)signaling was determined by PCR,western blotting,and tissue microarray.Cell viability and aflatoxin B1(AFB1)cytotoxicity were measured using the cell counting kit-8 assay.Target gene expression was evaluated using transient transfection and real time-PCR.The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.Results:HBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione Stransferase Mu 1(GSTM1)in cell lines.Activation of PxR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin(IL)-11:IL-11 receptor subunit alpha-1(IL11RA-1)-mediated inflammation in an HBx transgenic model.Conclusions:Our finding regarding AFB1 toxicity enhancement by an HBx-PxR-CYP3A4/GSTM1-KRASIL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.

关键词： Liver cancer Hepatitis B virus x protein Pregnane X receptor Aflatoxin B1 Hepatotoxicity

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Advances in drug resistance of triple negative breast cancer caused by Pregnane X receptor

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世界临床肿瘤学杂志:英文版 2023年第9期14卷 335-342页

作者： Zhou-Zhou Rao Zhong-Wen Tang Jie Wen Department of Physiology Hunan Normal University School of MedicineChangsha 410003Hunan ProvinceChina Department of Pediatric Orthopedics Hunan Provincial People’s Hospitalthe First Affiliated Hospital of Hunan Normal UniversityChangsha 410013Hunan ProvinceChina

Breast cancer is the most common malignancy in women worldwide.Triplenegative breast cancer(TNBC),refers breast cancer negative for estrogen receptor,progesterone receptor and human epidermal growth factor receptor 2,characterized by high drug resistance,high metastasis and high recurrence,treatment of which is a difficult problem in the clinical treatment of breast cancer.In order to better treat TNBC clinically,it is a very urgent task to explore the mechanism of TNBC resistance in basic breast cancer research.Pregnane X receptor(PxR)is a nuclear receptor whose main biological function is to participate in the metabolism,transport and clearance of allobiological agents in PxR.PxR plays an important role in drug metabolism and clearance,and PxR is highly expressed in tumor tissues of TNBC patients,which is related to the prognosis of breast cancer patients.This reviews synthesized the important role of PxR in the process of high drug resistance to TNBC chemotherapeutic drugs and related research progress.

关键词： Triple-negative breast cancer Pregnane X receptor Drug resistance Cytochrome P450 Uridinediphosphate glucuronyl transferases Glutathione transferases ATP-binding cassette transporter

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PxR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α-GLUT2 pathway

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2391-2405页

作者： Peihua Liu Ling Jiang Weimin Kong Qiushi xie Ping Li xiaonan Liu Jiayi Zhang Ming Liu Zhongjian Wang Liang Zhu Hanyu Yang Ying Zhou Jianjun Zou xiaodong Liu Li Liu Center of Drug Metabolism and Pharmacokinetics School of PharmacyChina Pharmaceutical UniversityNanjing 210009China Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical UniversityXuzhou 221004China Department of Clinical Pharmacology Nanjing First HospitalNanjing Medical UniversityNanjing 210006China

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the Pregnane X receptor(PxR), but the mechanism is unclear. Here, we report that PxR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha(HNF4 a)-glucose transporter 2(GLUT2) pathway. The PxR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4 a expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PxR downregulated GLUT2 and HNF4 a expression, while silencing PxR upregulated HNF4 a and GLUT2 expression.Silencing HNF4 a decreased GLUT2 expression, while overexpressing HNF4 a increased GLUT2 expression and glucose uptake. Silencing PxR or overexpressing HNF4 a reversed the atorvastatininduced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4 a mRNA expression, which could be attenuated by silencing PxR. Silencing HNF4 a downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4 a plasmid increased Slc2 a2 promoter activity. Hnf4 a silencing or pregnenolone-16 a-carbonitrile(PCN) suppressed the Slc2 a2 promoter activity by decreasing HNF4 a recruitment to the Slc2 a2 promoter. Liver-specific Hnf4 a deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4 a and GLUT2. In conclusion, PxR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4 aGLUT2 pathway. These results highlight the molecular mechanisms by which PxR activators induce hyperglycemia/diabetes.

关键词： Pregnane X receptor Hepatocyte nuclear factor4-alpha Glucose transporter 2 Hepatic glucose uptake Diabetes Drug-induced hyperglycemia

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Applanoids A—E as the First Examples of C-15/C-20 Michael Adducts in Ganoderma Triterpenoids and Their PxR Agonistic Activity

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Chinese Journal of Chemistry 2022年第22期40卷 2633-2641页

作者： Hai-Guo Su Hang-Fei Liang Gui-Lin Hu Lin Zhou xing-Rong Peng Hui-Chang Bi Ming-Hua Qiu Guangdong Provincial Key Laboratory of New Drug Design and Evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhouGuangdong510006China State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of BotanyChinese Academy of SciencesKunmingYunnan 650201China NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouGuangdong 510515China

Ganoderma triterpenoids(GTs),a class of major active constituents of Ganoderma fungi,possess diverse structures and remarkable activities.In the present study,nine new GTs,namely applanoids A—I(1—9),were isolated from the medicinal fungus of Ganoderma applanatum.Their structures including absolute configurations were established by comprehensive spectroscopic analyses and ECD calculation.Applanoids A—E(1—5)represent the first example of GTs with 6/6/5/6/5 pentacyclic system and the formation of the ether ring between C-15 and C-20 involves Michael addition reaction.Furthermore,compounds 1—8 were evaluated for their human Pregnane X receptor(hPxR)agonistic activity using dual-luciferase reporter gene assay,and the results showed that compounds 1,2 and 4 can dose-dependently activate hPxR.This investigation further illustrated the structural diversity of GTs and provided new insights for searching PxR agonists from GTs.

关键词： Ganoderma applanatum Lanostane triterpenoids Michael adducts Structure elucidation Pregnane X receptor

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Atypical functions of xenobiotic receptors in lipid and glucose metabolism

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Medical Review 2022年第6期2卷 611-624页

作者： Jingyuan Wang Peipei Lu Wen xie Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPAUSA Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261USA Department of Pharmacology and Chemical Biology University of PittsburghPittsburghPA 15261USA

xenobiotic receptors are traditionally defined as xenobiotic chemical-sensing receptors,the activation of which transcriptionally regulates the expression of enzymes and transporters involved in the metabolism and disposition of xenobiotics.Emerging evidence suggests that“xenobiotic receptors”also have diverse endobiotic functions,including their effects on lipid metabolism and energy metabolism.Dyslipidemia is a major risk factor for cardiovascular disease,diabetes,obesity,metabolic syndrome,stroke,nonalcoholic fatty liver disease(NAFLD),and nonalcoholic steatohepatitis(NASH).Understanding the molecular mechanism by which transcriptional factors,including the xenobiotic receptors,regulate lipid homeostasis will help to develop preventive and therapeutic approaches.This review describes recent advances in our understanding the atypical roles of three xenobiotic receptors:aryl hydrocarbon receptor(AhR),Pregnane X receptor(PxR),and constitutive androstane receptor(CAR),in metabolic disorders,with a particular focus on their effects on lipid and glucose metabolism.Collectively,the literatures suggest the potential values of AhR,PxR and CAR as therapeutic targets for the treatment of NAFLD,NASH,obesity and diabetes,and cardiovascular diseases.

关键词： aryl hydrocarbon receptor constitutive androstane receptor lipid metabolism Pregnane X receptor xenobiotic receptors

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Pregnenolone 16α-carbonitrile negatively regulates hippocampal cytochrome P450 enzymes and ameliorates phenytoin-induced hippocampal neurotoxicity

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Journal of Pharmaceutical Analysis 2023年第12期13卷 1510-1525页

作者： Shuai Zhang Tingting Wang Ye Feng Fei Li Aijuan Qu xiuchen Guan Hui Wang Dan xu Department of Obstetric Zhongnan Hospital of Wuhan UniversitySchool of Pharmaceutical SciencesWuhan UniversityWuhan430071China Department of Pharmacology School of Basic Medical SciencesWuhan UniversityWuhan430071China Hubei Provincial Key Laboratory of Developmentally Originated Disease Wuhan UniversityWuhan430071China Department of Endocrinology and Metabolic Disease The First Affiliated HospitalZhejiang University School of MedicineHangzhou310058China Frontiers Science Center for Disease-related Molecular Network West China HospitalSichuan UniversityChengdu610041China Department of Physiology and Pathophysiology School of Basic Medical SciencesCapital Medical UniversityBeijing100069China Key Laboratory of Remodeling-related Cardiovascular Diseases Ministry of EducationBeijing100069China Department of Orthodontics School of StomatologyCapital Medical UniversityBeijing100069China

The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme(CYP),which plays a crucial role in the metabolism of neurosteroids.The antiepileptic drug phenytoin(PHT)has been observed to induce neuronal side effects in patients,which could be attributed to its induction of CYP expression and testosterone(TES)metabolism in the hippocampus.While Pregnane X receptor(PxR)is widely known for its regulatory function of CYPs in the liver,we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile(PCN),a PxR agonist,has differential effects on CYP expression in the liver and hippocampus.Specifically,the PCN treatment resulted in the induction of cytochrome P450,family 3,subfamily a,polypeptide 11(CYP3A11),and CYP2B10 expression in the liver,while suppressing their expression in the hippocampus.Functionally,the PCN treatment protected mice from PHT-induced hippocampal nerve injury,which was accompanied by the inhibition of TES metabolism in the hippocampus.Mechanistically,we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent,rather than PxR independent,as demonstrated by genetic and pharmacological models.In conclusion,our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PxR.Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.

关键词： Pregnenolone 16a-carbonitrile Pregnane X receptor Hippocampus Glucocorticoid receptor Phenytoin sodium Neurotoxicity

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Activation of PxR causes drug interactions with Paxlovid in transgenic mice

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4502-4510页

作者： Saifei Lei Alice Guo Jie Lu Qian Qi Aaron S.Devanathan Junjie Zhu xiaochao Ma Center for Pharmacogenetics Department of Pharmaceutical SciencesSchool of PharmacyUniversity of PittsburghPittsburghPA 15261USA School of Nursing University of PennsylvaniaPhiladelphiaPA 19104USA Department of Pharmacy and Therapeutics School of PharmacyUniversity of PittsburghPittsburghPA 15261USA

Paxlovid is a nirmatrelvir(NMV)and ritonavir(RTV)co-packaged medication used for the treatment of coronavirus disease 2019(COVID-19).The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster.Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid.By using recombinant human cytochrome P450s(CYPs),we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism.The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice,which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV.Pregnane X receptor(PxR)is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression.We next explored the impact of drug-and herb-mediated PxR activation on Paxlovid metabolism in a transgenic mouse model expressing human PxR and CYP3A4/5.We found that PxR activation increased CYP3A4/5 expression,accelerated NMV metabolism,and reduced the systemic exposure of NMV.In summary,our work demonstrated that PxR activation can cause drug interactions with Paxlovid,suggesting that PxR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.

关键词： Paxlovid Nirmatrelvir Ritonavir Pregnane X receptor CYP3A4/5 Rifampicin Rhynchophylline Drug/herb-drug interactions

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Cisplatin increases carboxylesterases through increasing PxR mediated by the decrease of DEC1

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The Journal of Biomedical Research 2023年第6期37卷 431-447页

作者： Minqin xu Lihua Zhang Lan Lin Zhiyi Qiang Wei Liu Jian Yang Department of Pharmacology Nanjing Medical UniversityNanjingJiangsu 211166China

cis-Diamminedichloroplatinum(CDDP)is widely used for the treatment of various solid cancers.Here we reported that CDDP increased the expression and enzymatic activities of carboxylesterase 1(CES1)and carboxylesterase 2(CES2),along with the upregulation of Pregnane X receptor(PxR)and the downregulation of differentiated embryonic chondrocyte-expressed gene 1(DEC1)in human hepatoma cells,primary mouse hepatocytes,mouse liver and intestine.The overexpression or knockdown of PxR alone upregulated or downregulated the CES1 and CES2 expression,respectively.The increases in CES1 and CES2 expression levels induced by CDDP abolished or enhanced by PxR knockdown or overexpression,implying that CDDP induces carboxylesterases through the activation of PxR.Likewise,the overexpression or knockdown of DEC1 alone significantly decreased or increased PxR and its targets.Moreover,the increases of PxR and its targets induced by CDDP were abolished or alleviated by the overexpression or knockdown of DEC1.The overexpression or knockdown of DEC1 affected the response of PxR to CDDP,but not vice versa,suggesting that CDDP increases carboxylesterases by upregulating PxR mediated by the decrease of DEC1.In addition,CDDP did not increase DEC1 mRNA degradation but suppressed DEC1 promoter reporter activity,indicating that it suppresses DEC1 transcriptionally.The combined use of CDDP and irinotecan had a synergistic effect on two cell lines,especially when CDDP was used first.

关键词： cis-diamminedichloroplatinum Pregnane X receptor differentiated embryonic chondrocyte-expressed gene 1 carboxylesterase 1 carboxylesterase 2 irinotecan

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