{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:59:31Z","timestamp":1791269971838,"version":"4.1.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"18","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,5,4]]},"abstract":"<jats:p>\n                    In this study, we demonstrate that the pervasive xenobiotic methoxyacetic acid and the commonly prescribed anticonvulsant valproic acid, both short-chain fatty acids (SCFAs), dramatically increase cellular sensitivity to estrogens, progestins, and other nuclear hormone receptor ligands. These compounds do not mimic endogenous hormones but rather act to enhance the transcriptional efficacy of ligand activated nuclear hormone receptors by up to 8-fold\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Detailed characterization of their mode of action revealed that these SCFAs function as both activators of p42\/p44 mitogen-activated protein kinase and as inhibitors of histone deacetylases at doses that parallel known exposure levels. Our results define a class of compounds that possess a dual mechanism of action and function as hormone sensitizers. These findings prompt an evaluation of previously unrecognized drug\u2013drug interactions in women who are administered exogenous hormones while exposed to certain xenobiotic SCFAs. Furthermore, our study highlights the need to structure future screening programs to identify additional hormone sensitizers.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0402014101","type":"journal-article","created":{"date-parts":[[2004,4,21]],"date-time":"2004-04-21T20:13:32Z","timestamp":1082578412000},"page":"7199-7204","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":88,"title":["Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition"],"prefix":"10.1073","volume":"101","author":[{"given":"Michelle S.","family":"Jansen","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710; and National Center for Toxicogenomics, National Institute of Environmental Health Science, Research Triangle Park, NC 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan C.","family":"Nagel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710; and National Center for Toxicogenomics, National Institute of Environmental Health Science, Research Triangle Park, NC 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillippa J.","family":"Miranda","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710; and National Center for Toxicogenomics, National Institute of Environmental Health Science, Research Triangle Park, NC 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward K.","family":"Lobenhofer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710; and National Center for Toxicogenomics, National Institute of Environmental Health Science, Research Triangle Park, NC 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Afshari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710; and National Center for Toxicogenomics, National Institute of Environmental Health Science, Research Triangle Park, NC 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald P.","family":"McDonnell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710; and National Center for Toxicogenomics, National Institute of Environmental Health Science, Research Triangle Park, NC 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,4,21]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1186\/bcr467"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(01)00814-0"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.288.3.321"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.280.7.605"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012952"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1071884"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3190657"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.12.8226"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.39.22777"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.143.8.8942"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1530\/jrf.0.1050025"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1006\/faat.1997.2332"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420490318"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1080\/00039890109604050"},{"key":"e_1_3_2_15_2","first-page":"4470","volume":"51","year":"1991","unstructured":"Di Lorenzo, D., Albertini, A. & Zava, D. (1991) Cancer Res. 51, 4470-4475.1868468","journal-title":"Cancer Res."},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.139.9.6178"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.18.6122-6131.2001"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.3.1095-1111.2003"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.141.12.7836"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.3.1031"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101287200"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/90.21.1621"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/med.10017"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104309200"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10743"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg256"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5241.1491"},{"key":"e_1_3_2_28_2","first-page":"1882","volume":"14","year":"2000","unstructured":"Lee, H., Jiang, F., Wang, Q., Nicosia, S. V., Yang, J., Su, B. & Bai, W. (2000) Mol. Endocrinol. 14, 1882-1896.11075819","journal-title":"Mol. Endocrinol."},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.6.4475"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.14.5041-5047.2000"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a008804"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1080\/00039890209601424"},{"key":"e_1_3_2_33_2","unstructured":"National Institute for Occupational Safety and Health. (1991) Occupational Exposure to Ethylene Glycol Monomethyl Ether Ethylene Glycol Monoethyl Ether and Their Acetates (Natl. Inst. Health Bethesda) DHHS Publ. No. (NIH) 91-119."},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410390506"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(01)00806-3"},{"key":"e_1_3_2_36_2","first-page":"71541","volume":"63","year":"1998","unstructured":"Environmental Protection Agency (1998) Federal Register 63, 71541-71568.","journal-title":"Federal Register"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0402014101","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T22:02:49Z","timestamp":1650924169000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0402014101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,4,21]]},"references-count":36,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2004,5,4]]}},"alternative-id":["10.1073\/pnas.0402014101"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0402014101","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,4,21]]},"assertion":[{"value":"2004-02-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2004-04-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}