{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:02:29Z","timestamp":1779912149371,"version":"3.53.1"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Research Foundation of Shenzhen Longhua District Central Hospital","award":["202303"],"award-info":[{"award-number":["202303"]}]},{"name":"Shenzhen Longhua District Science and Technology Innovation Fund Projects","award":["2021105"],"award-info":[{"award-number":["2021105"]}]},{"name":"Shenzhen Longhua District Science and Technology Innovation Fund Projects","award":["2022045"],"award-info":[{"award-number":["2022045"]}]},{"name":"Shenzhen Longhua District Science and Technology Innovation Fund Projects","award":["2024074"],"award-info":[{"award-number":["2024074"]}]},{"name":"Zhanjiang Foundation of Science and Technology Project","award":["2023B01176"],"award-info":[{"award-number":["2023B01176"]}]},{"name":"Guangdong Provincial Hospital Pharmaceutical Research Foundation","award":["2023KJ07"],"award-info":[{"award-number":["2023KJ07"]}]},{"name":"Shenzhen Foundation of Science and Technology","award":["JCYJ20230807151308018"],"award-info":[{"award-number":["JCYJ20230807151308018"]}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"publisher","award":["2023A1515111116"],"award-info":[{"award-number":["2023A1515111116"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shenzhen Society of Health Economics Research Project","award":["202521"],"award-info":[{"award-number":["202521"]}]},{"name":"Key Disciplines of Clinical Pharmacy in Longhua District"},{"name":"Key Disciplines of Shenzhen Longhua District Central Hospital"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Voriconazole (VRC)-induced hepatotoxicity is an important consideration in the clinical application of voriconazole. This study explores the potential role of toll-like receptor (TLR) 4 activation on voriconazole-induced hepatotoxicity and its underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A model of VRC- and lipopolysaccharide (LPS)-induced hepatotoxicity was constructed using C57BL\/6 mice. Parallel experiments were carried out on wild-type mice (WT-LPS\u2009+\u2009VRC) and TLR4 knockout mice (KO-LPS\u2009+\u2009VRC) to examine the relationship between TLR4 activation and regulation of the farnesoid X receptor (FXR). Biochemical parameters and liver histopathology were observed. Quantitative real-time PCR and western blotting were used to assess gene and protein expression levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>Administering voriconazole twice within a 24-h period induces hepatotoxicity in mice under LPS-induced inflammatory conditions. VRC treatment caused darkening of the bile compared to normal mice. Conversely, KO-LPS\u2009+\u2009VRC mice maintained normal hepatocyte morphology and displayed light-coloured bile. The expression of p65 in the hepatocytes of KO-LPS\u2009+\u2009VRC was less than that of the WT-LPS\u2009+\u2009VRC. Additionally, the expression of nuclear FXR in the KO-LPS\u2009+\u2009VRC group was significantly higher than in the hepatocytes of WT-LPS\u2009+\u2009VRC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Activation of the TLR4 signalling pathway suppresses the activity of nuclear receptor FXR, impairs hepatic bile acid metabolism, impairs VRC excretion, and contributes to VRC hepatotoxicity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jpp\/rgaf060","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T10:05:02Z","timestamp":1752746702000},"page":"1542-1551","source":"Crossref","is-referenced-by-count":2,"title":["Toll-like receptor 4 activation potentiates voriconazole-induced hepatotoxicity via transcriptional repression of the farnesoid X receptor in murine hepatocytes"],"prefix":"10.1093","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4325-9907","authenticated-orcid":false,"given":"Xiaokang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Shenzhen Longhua District Central Hospital , 187 Guanlan West Road, Longhua District, Shenzhen 518110 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Macau University of Science and Technology , Shipaiwan Road, Macau 999078 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxian","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Ocean and Tropical Medicine, The Marine Biomedical Research Institute, Guangdong Medical University , Zhanjiang, Guangdong 524023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shenzhen Longhua District Central Hospital , 187 Guanlan West Road, Longhua District, Shenzhen 518110 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"2025110409535085300_ref1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/s41421-024-00758-w","article-title":"MAPK13 phosphorylates PHGDH and promotes its degradation via chaperone-mediated autophagy during liver injury","volume":"11","author":"Xing","year":"2025","journal-title":"Cell Discov"},{"key":"2025110409535085300_ref2","doi-asserted-by":"publisher","first-page":"3617","DOI":"10.2147\/DDDT.S475706","article-title":"The role of plasma trough concentration of voriconazole and voriconazole N-oxide in its hepatotoxicity in adult patients","volume":"18","author":"Cheng","year":"2024","journal-title":"Drug Des Devel Ther"},{"key":"2025110409535085300_ref3","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.clinthera.2025.01.006","article-title":"Potential of albumin-bilirubin score for estimating the voriconazole-induced hepatotoxicity undergoing therapeutic drug monitoring: a single-center retrospective cohort study","volume":"47","author":"Asai","year":"2025","journal-title":"Clin Ther"},{"key":"2025110409535085300_ref4","doi-asserted-by":"publisher","first-page":"1043836","DOI":"10.3389\/fphar.2022.1043836","article-title":"Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol"},{"key":"2025110409535085300_ref5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2024.116249","article-title":"Pharmacogene expression during progression of metabolic dysfunction-associated steatotic liver disease: studies on mRNA and protein levels and their relevance to drug treatment","volume":"228","author":"Govaere","year":"2024","journal-title":"Biochem Pharmacol"},{"key":"2025110409535085300_ref6","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1124\/dmd.107.018747","article-title":"Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer","volume":"36","author":"Morgan","year":"2008","journal-title":"Drug Metab Dispos"},{"key":"2025110409535085300_ref7","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1007\/s40264-025-01541-w","article-title":"The frequency of drug-induced liver injury due to antibiotics among hospitalised patients","volume":"48","author":"Bj\u00f6rnsson","year":"2025","journal-title":"Drug Saf"},{"key":"2025110409535085300_ref8","doi-asserted-by":"publisher","first-page":"1529660","DOI":"10.3389\/fimmu.2025.1529660","article-title":"1-methylnicotinamide modulates IL-10 secretion and voriconazole metabolism","volume":"16","author":"Deng","year":"2025","journal-title":"Front Immunol"},{"key":"2025110409535085300_ref9","doi-asserted-by":"publisher","first-page":"1522271","DOI":"10.3389\/fphar.2024.1522271","article-title":"Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway","volume":"15","author":"Wang","year":"2024","journal-title":"Front Pharmacol"},{"key":"2025110409535085300_ref10","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1186\/s12967-018-1533-4","article-title":"A strategy for designing voriconazole dosage regimens to prevent invasive pulmonary aspergillosis based on a cellular pharmacokinetics\/pharmacodynamics model","volume":"16","author":"Wang","year":"2018","journal-title":"J Transl Med"},{"key":"2025110409535085300_ref11","volume-title":"LiverTox: Clinical and Research Information on Drug-Induced Liver Injury","year":"2012"},{"key":"2025110409535085300_ref12","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1248\/bpb.b18-00028","article-title":"Dysregulation of BSEP and MRP2 may play an important role in isoniazid-induced liver injury via the SIRT1\/FXR pathway in rats and HepG2 cells","volume":"41","author":"Qu","year":"2018","journal-title":"Biol Pharm Bull"},{"key":"2025110409535085300_ref13","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1093\/toxsci\/kfw098","article-title":"Pyrazinamide induced rat cholestatic liver injury through inhibition of FXR regulatory effect on bile acid synthesis and transport","volume":"152","author":"Guo","year":"2016","journal-title":"Toxicol Sci"},{"key":"2025110409535085300_ref14","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1042\/CS20220674","article-title":"Potential therapeutic action of tauroursodeoxycholic acid against cholestatic liver injury via hepatic Fxr\/Nrf2 and CHOP-DR5-caspase-8 pathway","volume":"137","author":"Song","year":"2023","journal-title":"Clin Sci (Lond)"},{"key":"2025110409535085300_ref15","doi-asserted-by":"publisher","first-page":"481","DOI":"10.14218\/JCTH.2024.00024","article-title":"Astragalus polysaccharide enhances voriconazole metabolism under inflammatory conditions through the gut microbiota","volume":"12","author":"Wang","year":"2024","journal-title":"J Clin Transl Hepato"},{"key":"2025110409535085300_ref16","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.663325","article-title":"Bacteroides fragilis polysaccharide a ameliorates abnormal voriconazole metabolism accompanied with the inhibition of TLR4\/NF-\u03baB pathway","volume":"12","author":"Wang","year":"2021","journal-title":"Front Pharmacol"},{"key":"2025110409535085300_ref17","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1007\/s12072-021-10144-3","article-title":"Drug-induced liver injury: Asia Pacific Association of Study of liver consensus guidelines","volume":"15","author":"Devarbhavi","year":"2021","journal-title":"Hepatol Int"},{"key":"2025110409535085300_ref18","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1093\/jpp\/rgab025","article-title":"Effect of total glucosides of paeony and Tripterygium wilfordii polyglycosides on erythrocyte methotrexate polyglutamates in rats, analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry","volume":"73","author":"Wu","year":"2021","journal-title":"J Pharm Pharmacol"},{"key":"2025110409535085300_ref19","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1093\/jpp\/rgab112","article-title":"VX-765 ameliorates inflammation and extracellular matrix accumulation by inhibiting the NOX1\/ROS\/NF-\u03baB pathway in diabetic nephropathy","volume":"74","author":"Wang","year":"2022","journal-title":"J Pharm Pharmacol"},{"key":"2025110409535085300_ref20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2024.116989","article-title":"Triclosan exposure causes abnormal bile acid metabolism through IL-1\u03b2-NF-\u03baB-Fxr signaling pathway","volume":"284","author":"Liu","year":"2024","journal-title":"Ecotoxicol Environ Saf"},{"key":"2025110409535085300_ref21","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1093\/jpp\/rgae123","article-title":"Puerarin improves Dioscorea bulbifera L.-induced liver injury by regulating drug transporters and the Nrf2\/NF-\u03baB\/Bcl-2 signaling pathway","volume":"76","author":"Wang","year":"2024","journal-title":"J Pharm Pharmacol"},{"key":"2025110409535085300_ref22","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1124\/jpet.109.162651","article-title":"Intrinsic versus idiosyncratic drug-induced hepatotoxicity--two villains or one?","volume":"332","author":"Roth","year":"2010","journal-title":"J Pharmacol Exp Ther"},{"key":"2025110409535085300_ref23","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.it.2012.05.002","article-title":"Dissecting negative regulation of toll-like receptor signaling","volume":"33","author":"Kondo","year":"2012","journal-title":"Trends Immunol"},{"key":"2025110409535085300_ref24","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1007\/s12016-013-8402-y","article-title":"TLR2 and TLR4 in autoimmune diseases: a comprehensive review","volume":"47","author":"Liu","year":"2014","journal-title":"Clin Rev Allergy Immunol"},{"key":"2025110409535085300_ref25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.14218\/JCTH.2018.00042","article-title":"Mechanisms of hepatic cholestatic drug injury","volume":"7","author":"Kolari\u0107","year":"2019","journal-title":"J Clin Transl Hepato"},{"key":"2025110409535085300_ref26","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.mam.2017.06.001","article-title":"Mechanisms of bile acid mediated inflammation in the liver","volume":"56","author":"Li","year":"2017","journal-title":"Mol Asp Med"},{"key":"2025110409535085300_ref27","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1124\/mol.110.067256","article-title":"Itraconazole-induced cholestasis: involvement of the inhibition of bile canalicular phospholipid translocator MDR3\/ABCB4","volume":"79","author":"Yoshikado","year":"2011","journal-title":"Mol Pharmacol"},{"key":"2025110409535085300_ref28","doi-asserted-by":"publisher","first-page":"1511229","DOI":"10.3389\/fimmu.2024.1511229","article-title":"Gut microbiota trigger host liver immune responses that affect drug-metabolising enzymes","volume":"15","author":"Rao","year":"2024","journal-title":"Front Immunol"},{"key":"2025110409535085300_ref29","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1093\/jpp\/rgad115","article-title":"Differential effects of dietary polyphenols on oral pharmacokinetics of cyclin-dependent kinase inhibitors in rats: a mechanistic framework for in vitro-in vivo extrapolation","volume":"76","author":"Patil","year":"2024","journal-title":"J Pharm Pharmacol"},{"key":"2025110409535085300_ref30","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1093\/jpp\/rgae055","article-title":"Genipin improves obesity through promoting bile secretion and changing bile acids composition in diet-induced obese rats","volume":"76","author":"Guan","year":"2024","journal-title":"J Pharm Pharmacol"},{"key":"2025110409535085300_ref31","doi-asserted-by":"publisher","first-page":"5363","DOI":"10.1002\/ptr.8326","article-title":"Gardenia jasminoides Ellis. polysaccharides alleviated cholestatic liver injury by increasing the production of butyric acid and FXR activation","volume":"38","author":"Wang","year":"2024","journal-title":"Phytother Res"},{"key":"2025110409535085300_ref32","doi-asserted-by":"publisher","first-page":"5285","DOI":"10.1128\/AAC.00854-16","article-title":"Role of inflammatory and oxidative stress, cytochrome P450 2E1, and bile acid disturbance in rat liver injury induced by isoniazid and lipopolysaccharide cotreatment","volume":"60","author":"Hassan","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"key":"2025110409535085300_ref33","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1002\/jat.2979","article-title":"Lipopolysaccharide exposure augments isoniazide-induced liver injury","volume":"34","author":"Su","year":"2014","journal-title":"J Appl Toxicol"},{"key":"2025110409535085300_ref34","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1002\/cyto.a.22263","article-title":"Implication of hepatic transporters (MDR1 and MRP2) in inflammation-associated idiosyncratic drug-induced hepatotoxicity investigated by microvolume cytometry","volume":"83","author":"Saab","year":"2013","journal-title":"Cytometry A"}],"container-title":["Journal of Pharmacy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/77\/11\/1542\/64109359\/rgaf060.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/77\/11\/1542\/64109359\/rgaf060.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T14:54:02Z","timestamp":1762268042000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpp\/article\/77\/11\/1542\/8239715"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":34,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,8,22]]},"published-print":{"date-parts":[[2025,10,30]]}},"URL":"https:\/\/doi.org\/10.1093\/jpp\/rgaf060","relation":{},"ISSN":["0022-3573","2042-7158"],"issn-type":[{"value":"0022-3573","type":"print"},{"value":"2042-7158","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,11]]},"published":{"date-parts":[[2025,8,22]]}}}