Targeting the pregnane X receptor using microbial metabolite mimicry
Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.
Grantová podpora
P01 DK094779
NIDDK NIH HHS - United States
P30 DK041296
NIDDK NIH HHS - United States
R01 ES030197
NIEHS NIH HHS - United States
R35 ES028244
NIEHS NIH HHS - United States
HHSN261200800001C
NCI NIH HHS - United States
R01 CA161879
NCI NIH HHS - United States
R01 CA207416
NCI NIH HHS - United States
S10 RR029398
NCRR NIH HHS - United States
P30 CA013330
NCI NIH HHS - United States
HHSN261200800001E
NCI NIH HHS - United States
P30 ES007033
NIEHS NIH HHS - United States
R01 CA127231
NCI NIH HHS - United States
UL1 TR001073
NCATS NIH HHS - United States
P30 DK020541
NIDDK NIH HHS - United States
R01 DK080834
NIDDK NIH HHS - United States
R43 DK105694
NIDDK NIH HHS - United States
S10 OD019961
NIH HHS - United States
UL1 TR002556
NCATS NIH HHS - United States
PubMed
32153125
PubMed Central
PMC7136958
DOI
10.15252/emmm.201911621
Knihovny.cz E-zdroje
- Klíčová slova
- drugs, microbial metabolite, mimics, pregnane X receptor, therapy,
- MeSH
- cytokiny MeSH
- kultivované buňky MeSH
- lidé MeSH
- ligandy MeSH
- molekulární mimikry * MeSH
- myši MeSH
- organoidy MeSH
- pregnanový X receptor chemie MeSH
- střeva MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Názvy látek
- cytokiny MeSH
- ligandy MeSH
- pregnanový X receptor MeSH
The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR-specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.
Cincinnati Children's Hospital Medical Center Cincinnati OH USA
City University of New York City College and Graduate Center New York NY USA
Department of Biochemistry Albert Einstein College of Medicine Bronx NY USA
Department of Cell Biology and Genetics Palacký University Olomouc Czech Republic
Department of Chemistry City University of New York Hunter College New York NY USA
Department of Chemistry University of North Carolina Chapel Hill NC USA
Department of Environmental and Occupational Health Sciences University of Washington Seattle WA USA
Department of Microbiology and Immunology Drexel University College of Medicine Philadelphia PA USA
Department of Pathology Albert Einstein College of Medicine Bronx NY USA
Department of Pediatrics and Immunology University of Connecticut Farmington CT USA
Department of Pharmaceutical Sciences University of Connecticut Storrs CT USA
Department of Pharmacy Pharmaceutical Sciences University of Bari Aldo Moro Bari Italy
Department of Physiology and Pharmacology University of Calgary Calgary AB Canada
Molecular Biophysics Unit Indian Institute of Science Bangalore India
The Department of Biological and Environmental Engineering Cornell University Ithaca NY USA
The Department of Biology Johns Hopkins University Baltimore MD USA
The Department of Pathology New York University School of Medicine New York NY USA
Zobrazit více v PubMed
Abad‐Zapatero C, Blasi D (2011) Ligand efficiency indices (LEIs): more than a simple efficiency yardstick. Mol Inform 30: 122–132 PubMed
Abdel‐Razik A, Mousa N, Shabana W, Refaey M, Elzehery R, Elhelaly R, Zalata K, Abdelsalam M, Eldeeb AA, Awad M et al (2018) Rifaximin in nonalcoholic fatty liver disease: hit multiple targets with a single shot. Eur J Gastroenterol Hepatol 30: 1237–1246 PubMed
Andersson TB (2010) The application of HepRG cells in evaluation of cytochrome P450 induction properties of drug compounds. Methods Mol Biol 640: 375–387 PubMed
Aninat C, Piton A, Glaise D, Le Charpentier T, Langouet S, Morel F, Guguen‐Guillouzo C, Guillouzo A (2006) Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 34: 75–83 PubMed
Antherieu S, Chesne C, Li R, Guguen‐Guillouzo C, Guillouzo A (2012) Optimization of the HepaRG cell model for drug metabolism and toxicity studies. Toxicol In Vitro 26: 1278–1285 PubMed
Bartonkova I, Novotna A, Dvorak Z (2015) Novel stably transfected human reporter cell line AIZ‐AR as a tool for an assessment of human androgen receptor transcriptional activity. PLoS ONE 10: e0121316 PubMed PMC
Bartonkova I, Grycova A, Dvorak Z (2016) Profiling of vitamin D metabolic intermediates toward VDR using novel stable gene reporter cell lines IZ‐VDRE and IZ‐CYP24. Chem Res Toxicol 29: 1211–1222 PubMed
Berkhout TA, Simon HM, Patel DD, Bentzen C, Niesor E, Jackson B, Suckling KE (1996) The novel cholesterol‐lowering drug SR‐12813 inhibits cholesterol synthesis via an increased degradation of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase. J Biol Chem 271: 14376–14382 PubMed
Biber A, Fischer H, Romer A, Chatterjee SS (1998) Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers. Pharmacopsychiatry 31(Suppl 1): 36–43 PubMed
Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, Tilg H, Watson A, Wells JM (2014) Intestinal permeability–a new target for disease prevention and therapy. BMC Gastroenterol 14: 189 PubMed PMC
Brauze D, Zawierucha P, Kiwerska K, Bednarek K, Oleszak M, Rydzanicz M, Jarmuz‐Szymczak M (2017) Induction of expression of aryl hydrocarbon receptor‐dependent genes in human HepaRG cell line modified by shRNA and treated with beta‐naphthoflavone. Mol Cell Biochem 425: 59–75 PubMed PMC
Brave M, Lukin DJ, Mani S (2015) Microbial control of intestinal innate immunity. Oncotarget 6: 19962–19963 PubMed PMC
Brayton CF (1986) Dimethyl sulfoxide (DMSO): a review. Cornell Vet 76: 61–90 PubMed
Castro CA, Hogan JB, Benson KA, Shehata CW, Landauer MR (1995) Behavioral effects of vehicles: DMSO, ethanol, Tween‐20, Tween‐80, and emulphor‐620. Pharmacol Biochem Behav 50: 521–526 PubMed
Caujolle FM, Caujolle DH, Cros SB, Calvet MM (1967a) Limits of toxic and teratogenic tolerance of dimethyl sulfoxide. Ann N Y Acad Sci 141: 110–125 PubMed
Cavalluzzi MM, Mangiatordi GF, Nicolotti O, Lentini G (2017) Ligand efficiency metrics in drug discovery: the pros and cons from a practical perspective. Expert Opin Drug Discov 12: 1087–1104 PubMed
Chappell CL, Darkoh C, Shimmin L, Farhana N, Kim D‐K, Okhuysen PC, Hixson J (2016) Fecal indole as a biomarker of susceptibility to cryptosporidium infection. Infect Immun 84: 2299–2306 PubMed PMC
Cheng J, Krausz KW, Tanaka N, Gonzalez FJ (2012a) Chronic exposure to rifaximin causes hepatic steatosis in pregnane X receptor‐humanized mice. Toxicol Sci 129: 456–468 PubMed PMC
Cheng J, Shah YM, Gonzalez FJ (2012b) Pregnane X receptor as a target for treatment of inflammatory bowel disorders. Trends Pharmacol Sci 33: 323–330 PubMed PMC
Cobbold JFL, Atkinson S, Marchesi JR, Smith A, Wai SN, Stove J, Shojaee‐Moradie F, Jackson N, Umpleby AM, Fitzpatrick J et al (2018) Rifaximin in non‐alcoholic steatohepatitis: an open‐label pilot study. Hepatol Res 48: 69–77 PubMed
Delfosse V, Dendele B, Huet T, Grimaldi M, Boulahtouf A, Gerbal‐Chaloin S, Beucher B, Roecklin D, Muller C, Rahmani R et al (2015) Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds. Nat Commun 6: 8089 PubMed PMC
Delie F, Rubas W (1997) A human colonic cell line sharing similarities with enterocytes as a model to examine oral absorption: advantages and limitations of the Caco‐2 model. Crit Rev Ther Drug Carrier Syst 14: 221–286 PubMed
DeVoss J, Diehl L (2014) Murine models of inflammatory bowel disease (IBD): challenges of modeling human disease. Toxicol Pathol 42: 99–110 PubMed
Farrell DJ (2013) Rifaximin in the treatment of irritable bowel syndrome: is there a high risk for development of antimicrobial resistance? J Clin Gastroenterol 47: 205–211 PubMed
Feisst C, Werz O (2004) Suppression of receptor‐mediated Ca2+ mobilization and functional leukocyte responses by hyperforin. Biochem Pharmacol 67: 1531–1539 PubMed
Fernando EH, Dicay M, Stahl M, Gordon MH, Vegso A, Baggio C, Alston L, Lopes F, Baker K, Hirota S et al (2017) A simple, cost‐effective method for generating murine colonic 3D enteroids and 2D monolayers for studies of primary epithelial cell function. Am J Physiol Gastrointest Liver Physiol 313: G467–G475 PubMed
Fujii M, Matano M, Nanki K, Sato T (2015) Efficient genetic engineering of human intestinal organoids using electroporation. Nat Protoc 10: 1474–1485 PubMed
Gagnon M, Zihler Berner A, Chervet N, Chassard C, Lacroix C (2013) Comparison of the Caco‐2, HT‐29 and the mucus‐secreting HT29‐MTX intestinal cell models to investigate Salmonella adhesion and invasion. J Microbiol Methods 94: 274–279 PubMed
Galeotti N, Vivoli E, Bilia AR, Bergonzi MC, Bartolini A, Ghelardini C (2010) A prolonged protein kinase C‐mediated, opioid‐related antinociceptive effect of st John's Wort in mice. J Pain 11: 149–159 PubMed
Garbett NC, Chaires JB (2012) Thermodynamic studies for drug design and screening. Expert Opin Drug Discov 7: 299–314 PubMed PMC
Goodwin B, Hodgson E, Liddle C (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol Pharmacol 56: 1329–1339 PubMed
Gripon P, Rumin S, Urban S, Le Seyec J, Glaise D, Cannie I, Guyomard C, Lucas J, Trepo C, Guguen‐Guillouzo C (2002) Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci 99: 15655–15660 PubMed PMC
Guo Y, Zong S, Pu Y, Xu B, Zhang T, Wang B (2018) Advances in pharmaceutical strategies enhancing the efficiencies of oral colon‐targeted delivery systems in inflammatory bowel disease. Molecules 23: E1622 PubMed PMC
Gupta A, Mugundu GM, Desai PB, Thummel KE, Unadkat JD (2008) Intestinal human colon adenocarcinoma cell line LS180 is an excellent model to study pregnane X receptor, but not constitutive androstane receptor, mediated CYP3A4 and multidrug resistance transporter 1 induction: studies with anti‐human immunodeficiency virus protease inhibitors. Drug Metab Dispos 36: 1172–1180 PubMed
Huang H, Wang H, Sinz M, Zoeckler M, Staudinger J, Redinbo MR, Teotico DG, Locker J, Kalpana GV, Mani S (2007) Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene 26: 258–268 PubMed
Hung TV, Suzuki T (2018) Short‐chain fatty acids suppress inflammatory reactions in Caco‐2 cells and mouse colons. J Agric Food Chem 66: 108–117 PubMed
Hwang IK, Yoo KY, Li H, Park OK, Lee CH, Choi JH, Jeong YG, Lee YL, Kim YM, Kwon YG et al (2009) Indole‐3‐propionic acid attenuates neuronal damage and oxidative stress in the ischemic hippocampus. J Neurosci Res 87: 2126–2137 PubMed
Illes P, Brtko J, Dvorak Z (2015) Development and characterization of a human reporter cell line for the assessment of thyroid receptor transcriptional activity: a case of organotin endocrine disruptors. Journal of agricultural and food chemistry 63: 7074–7083 PubMed
Kandel BA, Thomas M, Winter S, Damm G, Seehofer D, Burk O, Schwab M, Zanger UM (2016) Genomewide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARalpha in primary human hepatocytes. Biochem Biophys Acta 1859: 1218–1227 PubMed
Kim JJ, Shajib MS, Manocha MM, Khan WI (2012) Investigating intestinal inflammation in DSS‐induced model of IBD. J Vis Exp 60: e3678 PubMed PMC
Kubesova K, Doricakova A, Travnicek Z, Dvorak Z (2016) Mixed‐ligand copper(II) complexes activate aryl hydrocarbon receptor AhR and induce CYP1A genes expression in human hepatocytes and human cell lines. Toxicol Lett 255: 24–35 PubMed
Kublbeck J, Anttila T, Pulkkinen JT, Honkakoski P (2015) Improved assays for xenosensor activation based on reverse transfection. Toxicol In Vitro 29: 1759–1765 PubMed
La Regina G, Bai R, Coluccia A, Famiglini V, Pelliccia S, Passacantilli S, Mazzoccoli C, Ruggieri V, Verrico A, Miele A et al (2015) New indole tubulin assembly inhibitors cause stable arrest of mitotic progression, enhanced stimulation of natural killer cell cytotoxic activity, and repression of hedgehog‐dependent cancer. J Med Chem 58: 5789–5807 PubMed PMC
Mahe MM, Sundaram N, Watson CL, Shroyer NF, Helmrath MA (2015) Establishment of human epithelial enteroids and colonoids from whole tissue and biopsy. J Vis Exp 97: e52483 PubMed PMC
Mani S (2016a) Chapter 23 – Regulation of host chromatin by bacterial metabolites In Chromatin signaling and diseases, Binda O, Fernandez‐Zapico ME. (eds), pp 423–442. Boston, MA: Academic Press;
Mani S (2017) Indole microbial metabolites: expanding and translating target(s). Oncotarget 8: 52014–52015 PubMed PMC
Mastropietro G, Tiscornia I, Perelmuter K, Astrada S, Bollati‐Fogolin M (2015) HT‐29 and Caco‐2 reporter cell lines for functional studies of nuclear factor kappa B activation. Mediators Inflamm 2015: 860534 PubMed PMC
McCue PP, Phang JM (2008) Identification of human intracellular targets of the medicinal Herb St. John's Wort by chemical‐genetic profiling in yeast. J Agric Food Chem 56: 11011–11017 PubMed PMC
Meng Z, Gwag T, Sui Y, Park SH, Zhou X, Zhou C (2019) The atypical antipsychotic quetiapine induces hyperlipidemia by activating intestinal PXR signaling. JCI Insight 4: 125657 PubMed PMC
Meyerholz DK, Beck AP (2018) Principles and approaches for reproducible scoring of tissue stains in research. Lab Invest 98: 844–855 PubMed
Murray IA, Flaveny CA, DiNatale BC, Chairo CR, Schroeder JC, Kusnadi A, Perdew GH (2010) Antagonism of aryl hydrocarbon receptor signaling by 6,2′,4′‐trimethoxyflavone. J Pharmacol Exp Ther 332: 135–144 PubMed PMC
Negres S, Scutari C, Ionica FE, Gonciar V, Velescu BS, Seremet OC, Zanfirescu A, Zbarcea CE, Stefanescu E, Ciobotaru E et al (2016) Influence of hyperforin on the morphology of internal organs and biochemical parameters, in experimental model in mice. Rom J Morphol Embryol 57: 663–673 PubMed
Nelson JD, Denisenko O, Bomsztyk K (2006) Protocol for the fast chromatin immunoprecipitation (ChIP) method. Nat Protoc 1: 179–185 PubMed
Ning L, Lou X, Zhang F, Xu G (2019) Nuclear receptors in the pathogenesis and management of inflammatory bowel disease. Mediators Inflamm 2019: 2624941 PubMed PMC
Novotna A, Pavek P, Dvorak Z (2011) Novel stably transfected gene reporter human hepatoma cell line for assessment of aryl hydrocarbon receptor transcriptional activity: construction and characterization. Environ Sci Technol 45: 10133–10139 PubMed
Novotna A, Pavek P, Dvorak Z (2012) Construction and characterization of a reporter gene cell line for assessment of human glucocorticoid receptor activation. Eur J Pharm Sci 47: 842–847 PubMed
Orans J, Teotico DG, Redinbo MR (2005) The nuclear xenobiotic receptor pregnane X receptor: recent insights and new challenges. Mol Endocrinol 19: 2891–2900 PubMed
Pastorkova B, Vrzalova A, Bachleda P, Dvorak Z (2017) Hydroxystilbenes and methoxystilbenes activate human aryl hydrocarbon receptor and induce CYP1A genes in human hepatoma cells and human hepatocytes. Food Chem Toxicol 103: 122–132 PubMed
Ranhotra HS, Flannigan KL, Brave M, Mukherjee S, Lukin DJ, Hirota SA, Mani S (2016) Xenobiotic receptor‐mediated regulation of intestinal barrier function and innate immunity. Nucl Receptor Res 3: 1–19 PubMed PMC
Saha S, Rajpal DK, Brown JR (2016) Human microbial metabolites as a source of new drugs. Drug Discovery Today 21: 692–698 PubMed
Scheer N, Ross J, Kapelyukh Y, Rode A, Wolf CR (2010) In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice. Drug Metab Dispos 38: 1046–1053 PubMed
Schiller CD, Kainz A, Mynett K, Gescher A (1992) Assessment of viability of hepatocytes in suspension using the MTT assay. Toxicol In Vitro 6: 575–578 PubMed
Schmittgen TD, Livak KJ (2008) Analyzing real‐time PCR data by the comparative C(T) method. Nat Protoc 3: 1101–1108 PubMed
Shan L (2010) 11C‐Labeled rifampicin In Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda, MD: National Center for Biotechnology Information (US) PubMed
Shukla SJ, Nguyen DT, Macarthur R, Simeonov A, Frazee WJ, Hallis TM, Marks BD, Singh U, Eliason HC, Printen J et al (2009) Identification of pregnane X receptor ligands using time‐resolved fluorescence resonance energy transfer and quantitative high‐throughput screening. Assay Drug Dev Technol 7: 143–169 PubMed PMC
Smith RP, Eckalbar WL, Morrissey KM, Luizon MR, Hoffmann TJ, Sun X, Jones SL, Force Aldred S, Ramamoorthy A, Desta Z et al (2014) Genome‐wide discovery of drug‐dependent human liver regulatory elements. PLoS Genet 10: e1004648 PubMed PMC
Smutny T, Mani S, Pavek P (2013) Post‐translational and post‐transcriptional modifications of pregnane X receptor (PXR) in regulation of the cytochrome P450 superfamily. Curr Drug Metab 14: 1059–1069 PubMed PMC
Soleymani S, Bahramsoltani R, Rahimi R, Abdollahi M (2017) Clinical risks of St John's Wort (Hypericum perforatum) co‐administration. Expert Opin Drug Metab Toxicol 13: 1047–1062 PubMed
Spence JR, Mayhew CN, Rankin SA, Kuhar MF, Vallance JE, Tolle K, Hoskins EE, Kalinichenko VV, Wells SI, Zorn AM et al (2011) Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro . Nature 470: 105–109 PubMed PMC
Staudinger JL, Goodwin B, Jones SA, Hawkins‐Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J et al (2001) The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA 98: 3369–3374 PubMed PMC
Tang C, Kakuta S, Shimizu K, Kadoki M, Kamiya T, Shimazu T, Kubo S, Saijo S, Ishigame H, Nakae S et al (2018) Suppression of IL‐17F, but not of IL‐17A, provides protection against colitis by inducing Treg cells through modification of the intestinal microbiota. Nat Immunol 19: 755–765 PubMed
Toporova L, Macejova D, Brtko J (2016) Radioligand binding assay for accurate determination of nuclear retinoid X receptors: a case of triorganotin endocrine disrupting ligands. Toxicol Lett 254: 32–36 PubMed
Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP, Qiu Z, Maher L, Redinbo MR, Phillips RS et al (2014) Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll‐like receptor 4. Immunity 41: 296–310 PubMed PMC
Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP et al (2015) Anticancer immunotherapy by CTLA‐4 blockade relies on the gut microbiota. Science 350: 1079–1084 PubMed PMC
Wallace BD, Betts L, Talmage G, Pollet RM, Holman NS, Redinbo MR (2013) Structural and functional analysis of the human nuclear xenobiotic receptor PXR in complex with RXRalpha. J Mol Biol 425: 2561–2577 PubMed PMC
Wang H, Venkatesh M, Li H, Goetz R, Mukherjee S, Biswas A, Zhu L, Kaubisch A, Wang L, Pullman J et al (2011) Pregnane X receptor activation induces FGF19‐dependent tumor aggressiveness in humans and mice. J Clin Investig 121: 3220–3232 PubMed PMC
Williamson B, Lorbeer M, Mitchell MD, Brayman TG, Riley RJ (2016) Evaluation of a novel PXR‐knockout in HepaRG cells. Pharmacol Res Perspect 4: e00264 PubMed PMC
Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B, Guzelian PS, Evans RM (2000) Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 14: 3014–3023 PubMed PMC
Yan L, Wang Y, Liu J, Nie Y, Zhong XB, Kan Q, Zhang L (2017) Alterations of histone modifications contribute to pregnane X receptor‐mediated induction of CYP3A4 by rifampicin. Mol Pharmacol 92: 113–123 PubMed PMC
Bacterial Indole as a Multifunctional Regulator of Klebsiella oxytoca Complex Enterotoxicity
Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs
Human microbial metabolite mimicry as a strategy to expand the chemical space of potential drugs