{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T21:09:21Z","timestamp":1782940161145,"version":"3.54.5"},"reference-count":116,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,4,27]],"date-time":"2019-04-27T00:00:00Z","timestamp":1556323200000},"content-version":"am","delay-in-days":365,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2018,4,27]],"date-time":"2018-04-27T00:00:00Z","timestamp":1524787200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006229","name":"Oak Ridge Institute for Science and Education","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006229","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000015","name":"U.S. Department of Energy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aliment Pharmacol Ther"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Bile acids play important roles in cholesterol metabolism and signal through farnesoid X receptor and G protein\u2010coupled receptors. Given their importance in liver biology, bile acid therapy enables therapeutic applications beyond the treatment of cholestatic liver disease. However, predicting hepatotoxicity of bile acids in humans is obscured due to inconsistent extrapolations of animal data to humans.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To review the evidence that could explain discordant bile acids hepatotoxicity observed in humans and animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Literature search was conducted in PubMed using keywords \u201cbile acid,\u201d \u201ctransporter,\u201d \u201chepatotoxicity,\u201d \u201cclinical study,\u201d \u201canimal study,\u201d \u201cspecies difference,\u201d \u201cmechanism,\u201d \u201cgenetic disorder.\u201d Relevant articles were selected for review.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Clinically significant hepatotoxicity was reported in response to certain bile acids, namely chenodeoxycholic acid, which was given a boxed warning for potential hepatotoxicity. The chemical structure, specifically the number and orientation of hydroxyl groups, significantly affects their hydrophobicity, an important factor in bile acid toxicity. Experimental studies show that hydrophobic bile acids can lead to liver injury through various mechanisms, such as death receptor signalling, mitochondrial dysfunction and inflammation. Although animal studies play a central role in investigating bile acid safety, there are considerable differences in bile acid composition, metabolism and hepatobiliary disposition across species. This does not allow appropriate safety inference, especially for predicting hepatotoxicity in humans. Exploring evidences stemming from inborn errors, genetic models of disease and toxicology studies further improves an understanding of bile acid hepatotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Species differences should be considered in the development of bile acid related therapeutics. Although the mechanism of bile acid hepatotoxicity is still not fully understood, continued mechanistic studies will deepen our understanding.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apt.14678","type":"journal-article","created":{"date-parts":[[2018,4,27]],"date-time":"2018-04-27T11:34:30Z","timestamp":1524828870000},"page":"1623-1638","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Review article: therapeutic bile acids and the risks for hepatotoxicity"],"prefix":"10.1111","volume":"47","author":[{"given":"K.","family":"Ashby","sequence":"first","affiliation":[{"name":"Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration Jefferson AR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. E.","family":"Navarro Almario","sequence":"additional","affiliation":[{"name":"Office of Computational Science Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Tong","sequence":"additional","affiliation":[{"name":"Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration Jefferson AR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Borlak","sequence":"additional","affiliation":[{"name":"Hannover Medical School Center of Pharmacology and Toxicology Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Mehta","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Inborn Error Products Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6453-2351","authenticated-orcid":false,"given":"M.","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration Jefferson AR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,4,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.72.121801.161712"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI106644"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.08.002"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R900012-JLR200"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.159.22.2647"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5418.1362"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-7568-6"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2013.151"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28709"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.113.008201"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25797"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28991"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2015.01.001"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R900010-JLR200"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2017.06.001"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25740"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00781.2006"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(02)00557-7"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.32982"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22771"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0088011"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000057"},{"key":"e_1_2_12_24_1","first-page":"509","volume-title":"Ganong's Review of Medical Physiology","author":"Barrett KE","year":"2012"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2017.09.008"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01296727"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)38331-0"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.15.1677"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197201062860101"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMct074694"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1046459"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24229"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2012.11.002"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-95-3-257"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197309272891303"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198412273112601"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840020611"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-121-3-199408010-00009"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(99)70351-3"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199105303242204"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.3109\/00365529409103624"},{"key":"e_1_2_12_42_1","unstructured":"Ursodiol.Drugs.com.https:\/\/www.drugs.com\/pro\/ursodiol.html. Accessed August 2016."},{"key":"e_1_2_12_43_1","unstructured":"URSO.DailyMed.https:\/\/dailymed.nlm.nih.gov\/dailymed\/drugInfo.cfm?setid=a061bb07-a85d-4b08-877f-ce02156f0de7. Accessed August 2016."},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajps.2016.05.006"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.12377"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2007.09.016"},{"key":"e_1_2_12_47_1","unstructured":"Obeticholic acid.DailyMed.https:\/\/dailymed.nlm.nih.gov\/dailymed\/drugInfo.cfm?setid=cdfbe0cd-eb15-45a1-ac17-531bcda21aec. Accessed August 2016."},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1509840"},{"key":"e_1_2_12_49_1","unstructured":"Norursodeoxycholic Acid in the Treatment of Primary Sclerosing Cholangitis (NUC\u20103).ClinicalTrials.gov.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01755507?term=NCT01755507&rank=1. Accessed August 2016."},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.48.1.75"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1081\/DMR-200033475"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.221564"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI105790"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01076210"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4274(92)90156-E"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0300-483X(74)90015-8"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(76)80409-X"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfr177"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2760(69)90092-7"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.30.9.997"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.051551698"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(75)80094-1"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfu228"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01891965"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2011.03.035"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.23582"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.119073"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00456.2003"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-011613-140021"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfq044"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2005.07.022"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1089\/aivt.2015.0014"},{"key":"e_1_2_12_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-010-9259-3"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-4-1"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/3034"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10713"},{"key":"e_1_2_12_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1147"},{"key":"e_1_2_12_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.499"},{"key":"e_1_2_12_79_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21062"},{"key":"e_1_2_12_80_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105300200"},{"key":"e_1_2_12_81_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI4765"},{"key":"e_1_2_12_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.10.155"},{"key":"e_1_2_12_83_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9914"},{"key":"e_1_2_12_84_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705671200"},{"key":"e_1_2_12_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4274(99)00113-7"},{"key":"e_1_2_12_86_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00482.2007"},{"key":"e_1_2_12_87_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/57.1.177"},{"key":"e_1_2_12_88_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.MPG.0000170600.80640.88"},{"key":"e_1_2_12_89_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.90780"},{"key":"e_1_2_12_90_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2010.11.026"},{"key":"e_1_2_12_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2013.09.023"},{"key":"e_1_2_12_92_1","doi-asserted-by":"publisher","DOI":"10.1586\/17474124.2015.1060855"},{"key":"e_1_2_12_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2015.01.015"},{"key":"e_1_2_12_94_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022094"},{"key":"e_1_2_12_95_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111301"},{"key":"e_1_2_12_96_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199405123301903"},{"key":"e_1_2_12_97_1","first-page":"851","article-title":"Toxicity of chenodeoxycholic acid in the nonhuman primate","volume":"77","author":"Morrissey K","year":"1975","journal-title":"Surgery"},{"key":"e_1_2_12_98_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(97)70239-7"},{"key":"e_1_2_12_99_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00972479"},{"key":"e_1_2_12_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(93)80087-K"},{"key":"e_1_2_12_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2008.08.018"},{"key":"e_1_2_12_102_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-4731(77)90277-1"},{"key":"e_1_2_12_103_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/56.3.511"},{"key":"e_1_2_12_104_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/128.11.1937"},{"key":"e_1_2_12_105_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215387"},{"key":"e_1_2_12_106_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-021580"},{"key":"e_1_2_12_107_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.52.10.1494"},{"key":"e_1_2_12_108_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1021211520034"},{"key":"e_1_2_12_109_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2003.50017"},{"key":"e_1_2_12_110_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.11.005"},{"key":"e_1_2_12_111_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2962"},{"key":"e_1_2_12_112_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu448"},{"key":"e_1_2_12_113_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510250635"},{"key":"e_1_2_12_114_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2918"},{"key":"e_1_2_12_115_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27240"},{"key":"e_1_2_12_116_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119355"},{"key":"e_1_2_12_117_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29516"}],"container-title":["Alimentary Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fapt.14678","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apt.14678","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/apt.14678","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/am-pdf\/10.1111\/apt.14678","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apt.14678","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T18:43:40Z","timestamp":1694371420000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/apt.14678"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,27]]},"references-count":116,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2018,6]]}},"alternative-id":["10.1111\/apt.14678"],"URL":"https:\/\/doi.org\/10.1111\/apt.14678","archive":["Portico"],"relation":{},"ISSN":["0269-2813","1365-2036"],"issn-type":[{"value":"0269-2813","type":"print"},{"value":"1365-2036","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,27]]},"assertion":[{"value":"2018-01-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-03-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-04-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}