{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:31:01Z","timestamp":1791959461335,"version":"4.3.4"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"6","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,3,13]]},"abstract":"<jats:p>\n                    The pregnane X receptor (PXR) is the molecular target for catatoxic\n steroids such as pregnenolone 16\u03b1-carbonitrile (PCN), which induce\n cytochrome P450 3A (\n                    <jats:italic>CYP3A<\/jats:italic>\n                    ) expression and protect the\n body from harmful chemicals. In this study, we demonstrate that PXR is\n activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto\n metabolite. Furthermore, we show that PXR regulates the expression of\n genes involved in the biosynthesis, transport, and metabolism of bile\n acids including cholesterol 7\u03b1-hydroxylase (\n                    <jats:italic>Cyp7a1<\/jats:italic>\n                    )\n and the Na\n                    <jats:sup>+<\/jats:sup>\n                    -independent organic anion transporter 2\n (\n                    <jats:italic>Oatp2<\/jats:italic>\n                    ). Finally, we demonstrate that activation of PXR\n protects against severe liver damage induced by LCA. Based on these\n data, we propose that PXR serves as a physiological sensor of LCA, and\n coordinately regulates gene expression to reduce the concentrations of\n this toxic bile acid. These findings suggest that PXR agonists may\n prove useful in the treatment of human cholestatic liver disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.051551698","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:41:48Z","timestamp":1027680108000},"page":"3369-3374","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1250,"title":["The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity"],"prefix":"10.1073","volume":"98","author":[{"given":"Jeff L.","family":"Staudinger","sequence":"first","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Goodwin","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey A.","family":"Jones","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Hawkins-Brown","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen I.","family":"MacKenzie","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"LaTour","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Liu","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis D.","family":"Klaassen","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen K.","family":"Brown","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Reinhard","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Willson","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly H.","family":"Koller","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Kliewer","sequence":"additional","affiliation":[{"name":"Departments of Molecular Endocrinology, Bioscience\r Support, Molecular Pharmacology, Metabolic Diseases,\r and Medicinal Chemistry, GlaxoSmithKline, Research\r Triangle Park, NC 27709; Curriculum in Genetics,\r Department of Medicine, University of North Carolina, Chapel Hill,\r NC 27599; and Department of Pharmacology and Toxicology,\r University of Kansas Medical Center, Kansas City, KS 66160"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,3,13]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600600102"},{"key":"e_1_3_3_2_2","first-page":"35","volume":"6","author":"Kourounakis P","year":"1977","unstructured":"P Kourounakis, H Selye, Y Tache Adv Steroid Biochem Pharmacol 6, 35\u201357 (1977).","journal-title":"Adv Steroid Biochem Pharmacol"},{"key":"e_1_3_3_3_2","first-page":"148","volume-title":"Microsomes and Drug Oxidations","author":"Guzelian P S","year":"1988","unstructured":"P S Guzelian Microsomes and Drug Oxidations, eds J O Miners, D J Birkett, R Drew, M McManus (Taylor and Francis, London), pp. 148\u2013155 (1988)."},{"key":"e_1_3_3_4_2","first-page":"241","volume-title":"Cytochromes P 450, metabolic and toxicological aspects","author":"Maurel P","year":"1996","unstructured":"P Maurel Cytochromes P 450, metabolic and toxicological aspects, ed C Ioannides (CRC, Boca Raton, FL), pp. 241\u2013270 (1996)."},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80900-9"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.21.12208"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.20.3195"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI3703"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1999.1307"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.14.1.0409"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/35019116"},{"key":"e_1_3_3_12_2","first-page":"88","volume":"25","author":"Fisher M M","year":"1971","unstructured":"M M Fisher, R Magnusson, K Miyai Lab Invest 25, 88\u201391 (1971).","journal-title":"Lab Invest"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/2101262a0"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199810223391707"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(96)06305-X"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1388-1981(99)00031-1"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)54816-X"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-141-36821"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.18.8424"},{"key":"e_1_3_3_20_2","first-page":"143","volume-title":"DNA Cloning","author":"Mohn A","year":"1995","unstructured":"A Mohn, B H Koller DNA Cloning, eds D M Glover, B D Hames (Oxford Univ. 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