{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:46:53Z","timestamp":1789055213283,"version":"build-2803163510"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"The National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173881"],"award-info":[{"award-number":["82173881"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"The National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82003840"],"award-info":[{"award-number":["82003840"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"The National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["8217130428"],"award-info":[{"award-number":["8217130428"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"The National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82025034"],"award-info":[{"award-number":["82025034"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program","doi-asserted-by":"publisher","award":["2017YFE0109900"],"award-info":[{"award-number":["2017YFE0109900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shenzhen Science and Technology Program","award":["KQTD20190929174023858"],"award-info":[{"award-number":["KQTD20190929174023858"]}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong","doi-asserted-by":"publisher","award":["2017A030311018"],"award-info":[{"award-number":["2017A030311018"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017688","name":"Key Laboratory Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2017B030314030"],"award-info":[{"award-number":["2017B030314030"]}],"id":[{"id":"10.13039\/501100017688","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program","award":["2017BT01Y093"],"award-info":[{"award-number":["2017BT01Y093"]}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"publisher","award":["2019A1515010247"],"award-info":[{"award-number":["2019A1515010247"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"publisher","award":["202102020717"],"award-info":[{"award-number":["202102020717"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002402","name":"Sun Yat-sen University","doi-asserted-by":"publisher","award":["22qntd4502"],"award-info":[{"award-number":["22qntd4502"]}],"id":[{"id":"10.13039\/501100002402","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Engineering and Technology Research Center for New drug Druggability Evaluation","award":["2017B090903004"],"award-info":[{"award-number":["2017B090903004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>St. John\u2019s wort (SJW) is a medicinal herb remedy for mild depression. However, long-term use of SJW has raised safety concerns in clinical practice because of drug-drug interactions. Excessive use of acetaminophen (APAP) causes severe hepatotoxicity, but whether SJW modulates APAP-induced liver injury remains unclear. In this study, the effect of long-term SJW administration on APAP-induced acute hepatotoxicity and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated that SJW exacerbates APAP-induced toxicity. Moreover, SJW markedly promoted glutathione depletion and increased the levels of the APAP-cysteine and APAP-N-acetylcysteinyl adducts in mice, which enhanced APAP metabolic activation and aggravated APAP-induced liver injury. To further elucidate APAP metabolic activation in liver injury induced by SJW, the activities and expression levels of CYP2E1 and CYP3A were measured. The results showed that the activities and expression levels of CYP2E1 and CYP3A were increased after SJW treatment. Furthermore, the PXR-CYP signaling pathway was activated by SJW, and its downstream target genes were upregulated. Collectively, this study demonstrated that the long-term administration of SJW extract led to the metabolic activation of APAP and significantly exacerbated APAP-induced liver injury, which may suggest caution for the clinical use of SJW and APAP.<\/jats:p>","DOI":"10.1093\/toxsci\/kfac094","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T13:32:52Z","timestamp":1662643972000},"page":"54-63","source":"Crossref","is-referenced-by-count":14,"title":["St. John\u2019s Wort Exacerbates Acetaminophen-Induced Liver Injury by Activation of PXR and CYP-Mediated Bioactivation"],"prefix":"10.1093","volume":"190","author":[{"given":"Yiming","family":"Jiang","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University , 510006 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University , 510006 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaofei","family":"Song","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University , 510006 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shicheng","family":"Fan","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University , 510006 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Gao","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University , 510006 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University , 510006 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Huang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University , 510006 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huichang","family":"Bi","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , 510515 Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"2022102808010430800_kfac094-B1","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1208\/s12248-009-9146-8","article-title":"Herb-drug interactions with St John\u2019s wort (Hypericum perforatum): An update on clinical observations","volume":"11","author":"Borrelli","year":"2009","journal-title":"AAPS J"},{"key":"2022102808010430800_kfac094-B2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/toxsci\/66.1.27","article-title":"St. John\u2019s wort extract induces CYP3A and CYP2E1 in the Swiss Webster mouse","volume":"66","author":"Bray","year":"2002","journal-title":"Toxicol. Sci"},{"key":"2022102808010430800_kfac094-B3","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1124\/dmd.31.6.798","article-title":"Hepatobiliary excretion of acetaminophen glutathione conjugate and its derivatives in transport-deficient (TR-) hyperbilirubinemic rats","volume":"31","author":"Chen","year":"2003","journal-title":"Drug Metab. Dispos"},{"key":"2022102808010430800_kfac094-B4","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1124\/dmd.31.7.908","article-title":"Nuclear receptor, pregname X receptor, is required for induction of UDP-glucuronosyltranferases in mouse liver by pregnenolone-16 alpha-carbonitrile","volume":"31","author":"Chen","year":"2003","journal-title":"Drug Metab. Dispos"},{"key":"2022102808010430800_kfac094-B5","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.bcp.2012.01.030","article-title":"Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters","volume":"83","author":"Chen","year":"2012","journal-title":"Biochem. Pharmacol"},{"key":"2022102808010430800_kfac094-B6","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1124\/dmd.109.027565","article-title":"Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity","volume":"37","author":"Cheng","year":"2009","journal-title":"Drug Metab. Dispos"},{"key":"2022102808010430800_kfac094-B7","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jchromb.2015.01.028","article-title":"Quantification of a biomarker of acetaminophen protein adducts in human serum by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Clinical and animal model applications","volume":"985","author":"Cook","year":"2015","journal-title":"J. Chromatography B Analyt Technol Biomed Life Sci"},{"key":"2022102808010430800_kfac094-B8","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jphotobiol.2008.01.011","article-title":"Hypericin phototoxicity induces different modes of cell death in melanoma and human skin cells","volume":"91","author":"Davids","year":"2008","journal-title":"J. Photochem. Photobiol. B"},{"key":"2022102808010430800_kfac094-B9","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1007\/s10620-008-0477-6","article-title":"The effect of Hypericum perforatum (St. John\u2019s wort) on experimental colitis in rat","volume":"54","author":"Dost","year":"2009","journal-title":"Dig. Dis. Sci"},{"key":"2022102808010430800_kfac094-B10","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s13181-015-0476-x","article-title":"Confirming the causative role of acetaminophen in indeterminate acute liver failure using acetaminophen-cysteine adducts","volume":"11","author":"Frey","year":"2015","journal-title":"J. Med. Toxicol"},{"key":"2022102808010430800_kfac094-B11","doi-asserted-by":"crossref","first-page":"12331","DOI":"10.1038\/s41598-017-11811-y","article-title":"MicroRNA regulation of CYP 1A2, CYP3A4 and CYP2E1 expression in acetaminophen toxicity","volume":"7","author":"Gill","year":"2017","journal-title":"Sci. Rep"},{"key":"2022102808010430800_kfac094-B12","first-page":"91","article-title":"Species variation in toxication and detoxication of acetaminophen in vivo: A comparative study of biliary and urinary excretion of acetaminophen metabolites","volume":"244","author":"Gregus","year":"1988","journal-title":"J. Pharmacol. Exp. Ther"},{"key":"2022102808010430800_kfac094-B13","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1016\/j.jfda.2017.11.007","article-title":"PXR as a mediator of herb-drug interaction","volume":"26","author":"Hogle","year":"2018","journal-title":"J. Food Drug Anal"},{"key":"2022102808010430800_kfac094-B14","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/toxsci\/kfaa002","article-title":"Novel therapeutic approaches against acetaminophen-induced liver injury and acute liver failure","volume":"174","author":"Jaeschke","year":"2020","journal-title":"Toxicol. Sci"},{"key":"2022102808010430800_kfac094-B15","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/toxsci\/kfu216","article-title":"Schisandrol B protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of liver regeneration","volume":"143","author":"Jiang","year":"2015","journal-title":"Toxicol. Sci"},{"key":"2022102808010430800_kfac094-B16","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/hep.30131","article-title":"Pregnane X receptor regulates liver size and liver cell fate by yes-associated protein activation in mice","volume":"69","author":"Jiang","year":"2019","journal-title":"Hepatology"},{"key":"2022102808010430800_kfac094-B17","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s13181-019-00740-z","article-title":"The effect of 4-methylpyrazole on oxidative metabolism of acetaminophen in human volunteers","volume":"16","author":"Kang","year":"2020","journal-title":"J. Med. Toxicol"},{"key":"2022102808010430800_kfac094-B18","first-page":"CD000448","article-title":"St John\u2019s wort for major depression","volume":"2008","author":"Linde","year":"2008","journal-title":"Cochrane Database Syst. Rev"},{"key":"2022102808010430800_kfac094-B19","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1016\/0140-6736(90)93063-U","article-title":"Management of paracetamol poisoning complicated by enzyme induction due to alcohol or drugs","volume":"335","author":"McClements","year":"1990","journal-title":"Lancet"},{"key":"2022102808010430800_kfac094-B20","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1007\/s11095-013-1007-6","article-title":"Metabolism and disposition of acetaminophen: Recent advances in relation to hepatotoxicity and diagnosis","volume":"30","author":"McGill","year":"2013","journal-title":"Pharm. Res"},{"key":"2022102808010430800_kfac094-B21","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1159\/000455524","article-title":"Metabolism of a glutathione conjugate in human fetal and adult tissues","volume":"1","author":"Moldeus","year":"1980","journal-title":"Dev. Pharmacol. Ther"},{"key":"2022102808010430800_kfac094-B22","doi-asserted-by":"crossref","first-page":"7500","DOI":"10.1073\/pnas.130155097","article-title":"St. John\u2019s wort induces hepatic drug metabolism through activation of the pregnane X receptor","volume":"97","author":"Moore","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022102808010430800_kfac094-B23","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.clpt.2004.01.014","article-title":"Effect of St. John\u2019s wort dose and preparations on the pharmacokinetics of digoxin","volume":"75","author":"Mueller","year":"2004","journal-title":"Clin. Pharmacol. Ther"},{"key":"2022102808010430800_kfac094-B24","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1111\/bph.14936","article-title":"Clinical relevance of St. John\u2019s wort drug interactions revisited","volume":"177","author":"Nicolussi","year":"2020","journal-title":"Br. J. Pharmacol"},{"key":"2022102808010430800_kfac094-B25","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1021\/tx4001013","article-title":"Disruption of thioredoxin reductase L protects mice from acute acetaminophen-induced hepatotoxicity through enhanced NRF2 activity","volume":"26","author":"Patterson","year":"2013","journal-title":"Chem. Res. Toxicol"},{"key":"2022102808010430800_kfac094-B26","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/hep.25645","article-title":"Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity","volume":"56","author":"Patterson","year":"2012","journal-title":"Hepatology"},{"key":"2022102808010430800_kfac094-B27","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1046\/j.1365-2125.2003.02005.x","article-title":"Interaction of St John\u2019s wort with low-dose oral contraceptive therapy: A randomized controlled trial","volume":"56","author":"Pfrunder","year":"2003","journal-title":"Br. J. Clin. Pharmacol"},{"key":"2022102808010430800_kfac094-B28","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/S0140-6736(99)05712-8","article-title":"Indinavir concentrations and St John\u2019s wort","volume":"355","author":"Piscitelli","year":"2000","journal-title":"Lancet"},{"key":"2022102808010430800_kfac094-B29","doi-asserted-by":"crossref","first-page":"3869","DOI":"10.3390\/molecules19043869","article-title":"Interaction between different extracts of Hypericum perforatum L. from Serbia and pentobarbital, diazepam and paracetamol","volume":"19","author":"Raskovic","year":"2014","journal-title":"Molecules"},{"key":"2022102808010430800_kfac094-B30","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/ptr.5050","article-title":"Hypericum perforatum: Pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions","volume":"28","author":"Russo","year":"2014","journal-title":"Phytother. Res"},{"key":"2022102808010430800_kfac094-B31","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.jep.2010.07.034","article-title":"A review of the antibacterial activity of Hypericum perforatum L","volume":"131","author":"Saddiqe","year":"2010","journal-title":"J. Ethnopharmacol"},{"key":"2022102808010430800_kfac094-B32","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S1474-4422(02)00129-1","article-title":"St John\u2019s wort for the treatment of depression","volume":"1","author":"Shelton","year":"2002","journal-title":"Lancet. Neurol"},{"key":"2022102808010430800_kfac094-B33","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.fct.2004.02.012","article-title":"St. John\u2019s wort (Hypericum perforatum) induces overexpression of multidrug resistance protein 2 (MRP2) in rats: A 30-day ingestion study. Food and chemical toxicology: An international journal published for the British Industrial","volume":"42","author":"Shibayama","year":"2004","journal-title":"Food Chem. Toxicol"},{"key":"2022102808010430800_kfac094-B34","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/0002-9343(92)90687-7","article-title":"Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine","volume":"93","author":"Shriner","year":"1992","journal-title":"Am. J. Med"},{"key":"2022102808010430800_kfac094-B35","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1080\/17425255.2017.1378342","article-title":"Clinical risks of St John\u2019s wort (Hypericum perforatum) co-administration","volume":"13","author":"Soleymani","year":"2017","journal-title":"Expert Opin. Drug Metab. Toxicol"},{"key":"2022102808010430800_kfac094-B36","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.clpt.2003.09.014","article-title":"St John\u2019s wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole","volume":"75","author":"Wang","year":"2004","journal-title":"Clin. Pharmacol. Ther"},{"key":"2022102808010430800_kfac094-B37","first-page":"1827","article-title":"Role of the nuclear receptor pregnane X receptor in acetaminophen hepatotoxicity","volume":"33","author":"Wolf","year":"2005","journal-title":"Drug Metab. Dispos"},{"key":"2022102808010430800_kfac094-B38","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1038\/sj.bjp.0707685","article-title":"Effects of St John\u2019s wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide","volume":"153","author":"Xu","year":"2008","journal-title":"Br. J. Pharmacol"},{"key":"2022102808010430800_kfac094-B39","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.redox.2018.04.019","article-title":"Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions","volume":"17","author":"Yan","year":"2018","journal-title":"Redox. Biol"},{"key":"2022102808010430800_kfac094-B40","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.apsb.2020.06.016","article-title":"SIRT6 as a key event linking P53 and NRF2 counteracts APAP-induced hepatotoxicity through inhibiting oxidative stress and promoting hepatocyte proliferation","volume":"11","author":"Zhou","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"issue":"Suppl. 1","key":"2022102808010430800_kfac094-B41","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1002\/ptr.2852","article-title":"Protective effects of a flavonoid-rich extract of Hypericum perforatum L. Against hydrogen peroxide-induced apoptosis in PC12 cells","volume":"2","author":"Zou","year":"2010","journal-title":"Phytother. Res"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfac094\/45955145\/kfac094.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/190\/1\/54\/46663990\/kfac094.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/190\/1\/54\/46663990\/kfac094.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T12:10:03Z","timestamp":1666959003000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/190\/1\/54\/6694059"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,9,8]]},"published-print":{"date-parts":[[2022,10,27]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfac094","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,11,1]]},"published":{"date-parts":[[2022,9,8]]}}}