{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:19:17Z","timestamp":1789510757850,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Progress in understanding the mechanisms of the idiosyncratic drug induced liver injury (iDILI) was highlighted in a scientometric investigation on the knowledge mapping of iDILI throughout the world, but uncertainty remained on metabolic risk factors of iDILI, the focus of the present review article. For the first time, a quantitative analysis of 3312 cases of iDILI assessed for causality with RUCAM (Roussel Uclaf Causality Assessment Method) showed that most drugs (61.1%) were metabolized by cytochrome P450 (CYP) isoforms: 49.6% by CYP 3A4\/5, 24.6% by CYP 2C9, 13.2% by CYP 2E1, 7.3% by CYP 2C19, 3.5% by CYP 1A2 and 1.8% by CYP 2D6. Other studies showed high OR (odds ratio) for drugs metabolized by unspecified CYPs but the iDILI cases were not assessed for causality with RUCAM, a major shortcoming. In addition to critical comments on methodological flaws, several risk factors of iDILI were identified such as high but yet recommended daily drug doses, actual daily drug doses taken by the patients, hepatic drug metabolism and drug lipophilicity. These risk factors are subject to controversies by many experts seen critically also by others who outlined that none of these medication characteristics is able to predict iDILI with high confidence, leading to the statement of an outstanding caveat. It was also argued that all previous studies lacked comprehensive data because the number of examined drugs was relatively small as compared to the number of approved new molecular entities or currently used oral prescription drugs. In conclusion, trends are evident that some metabolic parameters are likely risk factors of iDILI but strong evidence can only be achieved when methodological issues will be successfully met.<\/jats:p>","DOI":"10.3390\/ijms22073441","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T13:17:53Z","timestamp":1616764673000},"page":"3441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Idiosyncratic Drug Induced Liver Injury, Cytochrome P450, Metabolic Risk Factors and Lipophilicity: Highlights and Controversies"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8910-1200","authenticated-orcid":false,"given":"Rolf","family":"Teschke","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt\/Main, 60323 Frankfurt\/Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7580-1505","authenticated-orcid":false,"given":"Gaby","family":"Danan","sequence":"additional","affiliation":[{"name":"Pharmacovigilance Consultancy, F-75020 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Danan, G. (2020). Worldwide use of RUCAM for causality assessment in 81,856 DILI and 14,029 HILI cases published 1993\u2014Mid 2020: A comprehensive analysis. Medicines, 7.","DOI":"10.3390\/medicines7100062"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"842","DOI":"10.3389\/fphar.2020.00842","article-title":"Knowledge mapping of drug-induced liver injury: A scientometric investigation (2010\u20132019)","volume":"11","author":"Ke","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_3","first-page":"1169","article-title":"Review. Top-ranking drugs out of 3312 drug-induced liver injury cases evaluated by the Roussel Uclaf Causality Assessment Method","volume":"14","author":"Teschke","year":"2018","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"837","DOI":"10.3389\/fphar.2019.00837","article-title":"Mechanistic studies of idiosyncratic DILI: Clinical implications","volume":"10","author":"Uetrecht","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Uetrecht, J. (2021). Idiosyncratic drug induced liver injury (DILI): Unresolved basic issues. Diagnostics, 11.","DOI":"10.3390\/diagnostics11030458"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/0895-4356(93)90101-6","article-title":"Causality assessment of adverse reactions to drugs\u2014I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries","volume":"46","author":"Danan","year":"1993","journal-title":"J. Clin. Epidemiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/0895-4356(93)90102-7","article-title":"Causality assessment of adverse reactions of drugs\u2014II. An original model for validation of drug causality assessment methods: Case reports with positive rechallenge","volume":"46","author":"Benichou","year":"1993","journal-title":"J. Clin. Epidemiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Danan, G., and Teschke, R. (2016). RUCAM in drug and herb induced liver injury: The update. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010014"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1124\/dmd.113.056267","article-title":"High daily dose and being a substrate of cytochrome P450 enzymes are two important predictors of drug-induced liver injury","volume":"42","author":"Yu","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/toxsci\/65.2.166","article-title":"Mechanisms of hepatotoxicity","volume":"65","author":"Jaeschke","year":"2002","journal-title":"Toxicol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9176937","DOI":"10.1155\/2017\/9176937","article-title":"Idiosyncratic drug-induced liver injury (IDILI): Potential mechanisms and predictive assays","volume":"2017","author":"Roth","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102","DOI":"10.4103\/0019-5359.30351","article-title":"Cytochrome P450 enzyme isoforms and their therapeutic implications: An update","volume":"61","author":"Kalra","year":"2007","journal-title":"Indian J. Med. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1124\/dmd.116.071753","article-title":"Cytochrome P450 and non-cytochrome P450 oxidative metabolism: Contributions to the pharmacokinetics, safety, and efficacy of xenobiotics","volume":"44","author":"Foti","year":"2016","journal-title":"Drug Metab. Dispos."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"730","DOI":"10.3389\/fphar.2019.00730","article-title":"Idiosyncratic DILI: Analysis of 46,266 cases assessed for causality by RUCAM and published from 2014 to early 2019","volume":"10","author":"Teschke","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/jcph.23","article-title":"Drug-induced liver injury: The role of drug metabolism and transport","volume":"53","author":"Corsini","year":"2013","journal-title":"J. Clin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Johansson, I., and Ingelman-Sundberg, M. (2011). Genetic polymorphism and toxicology\u2014With emphasis on cytochrome P450. Toxicol. Sci., 120.","DOI":"10.1093\/toxsci\/kfq374"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/jbt.20174","article-title":"Mechanisms of cytochrome P450 substrate oxidation: MiniReview","volume":"21","author":"Guengerich","year":"2007","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.3748\/wjg.15.2817","article-title":"Drug-induced liver injury: Is it somehow foreseeable?","volume":"15","author":"Tarantino","year":"2009","journal-title":"World J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1146\/annurev.pharmtox.47.120505.105150","article-title":"Idiosyncratic drug reactions: Current understanding","volume":"47","author":"Uetrecht","year":"2007","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1021\/tx980249i","article-title":"New concepts in immunology relevant to idiosyncratic drug reaction: The \u201cdanger hypothesis\u201d and innate immune system","volume":"12","author":"Uetrecht","year":"1999","journal-title":"Chem. Res. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"93","DOI":"10.12970\/2308-8044.2020.08.12","article-title":"Liver injury by drugs metabolized via cytochrome P450","volume":"8","author":"Teschke","year":"2020","journal-title":"J. Mod. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/hep.23317","article-title":"Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events","volume":"51","author":"Lammert","year":"2010","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1002\/hep.22272","article-title":"Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: Search for signals","volume":"47","author":"Lammert","year":"2008","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1002\/hep.26208","article-title":"High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury","volume":"58","author":"Chen","year":"2013","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17031","DOI":"10.18632\/oncotarget.4400","article-title":"A comprehensive study of the association between drug hepatotoxicity and daily dose, liver metabolism, and lipophilicity using 975 oral medications","volume":"6","author":"Weng","year":"2015","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"McEuen, K., Borlak, J., Tong, W., and Chen, M. (2017). Associations of drug lipophilicity and extent of metabolism with drug-induced liver injury. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071335"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bj\u00f6rnsson, E.S. (2016). Hepatotoxicity by drugs: The most common implicated agents. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17020224"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1002\/hep.28323","article-title":"Categorization of drugs implicated in causing liver injury: Critical assessment based on published case reports","volume":"63","author":"Hoofnagle","year":"2016","journal-title":"Hepatology"},{"key":"ref_29","first-page":"1","article-title":"Selected highlights and controversies of drug-induced liver injury from the recent literature","volume":"1","author":"Rosenberg","year":"2020","journal-title":"World J. Gastroenterol. Hepatol. Endosc. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1021\/tx960083q","article-title":"Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis","volume":"9","author":"Bourdi","year":"1996","journal-title":"Chem. Res. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1097\/MEG.0b013e3283036768","article-title":"Kava hepatotoxicity: A clinical survey and critical analysis of 26 suspected cases","volume":"20","author":"Teschke","year":"2008","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S1665-2681(19)31634-5","article-title":"Kava hepatotoxicity\u2014A clinical review","volume":"9","author":"Teschke","year":"2010","journal-title":"Ann. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1002\/lt.20204","article-title":"Liver transplantation for acute liver failure from drug induced liver injury in the United States","volume":"10","author":"Russo","year":"2004","journal-title":"Liver Transpl."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.jhep.2011.07.023","article-title":"Hepatotoxicity associated with statins: Reports of idiosyncratic liver injury post-marketing","volume":"56","author":"Jacobsen","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.jhep.2012.04.001","article-title":"Reply to: \u201cstatin hepatotoxicity and the dilemma of causality in rare hepatic adverse drug reactions","volume":"57","author":"Bader","year":"2012","journal-title":"\u201d J. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.jhep.2011.08.016","article-title":"Yes! Statins can be given to liver patients","volume":"56","author":"Bader","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.jhep.2012.03.010","article-title":"Statin hepatotoxicity and the dilemma of causality in rare hepatic adverse drug reactions","volume":"57","author":"Schulze","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/S1665-2681(19)30943-3","article-title":"Hepatotoxicity associated with statins","volume":"11","author":"Teschke","year":"2012","journal-title":"Ann. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Danan, G. (2021). DILI cases in registries and databases: An analysis of quality. Int. J. Gastroenterol. Hepatol. Dis.","DOI":"10.2174\/2666290601666210325091553"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/ajg.2010.102","article-title":"The myth of statin-induced hepatotoxicity","volume":"105","author":"Bader","year":"2010","journal-title":"Am. J. Gastroenterol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Jee, A., Sernoskie, S.C., and Uetrecht, J. (2021). Idiosyncratic drug-induced liver injury: Mechanistic and clinical challenges. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062954"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1038\/s41591-020-1023-0","article-title":"Polygenic architecture informs potential vulnerability to drug-induced liver injury","volume":"26","author":"Koido","year":"2020","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lauschke, V.M. (2021). Toxocogenomics of drug induced liver injury\u2014From mechanistic understanding to early prediction. Drug Metab. Rev.","DOI":"10.1080\/03602532.2021.1894571"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"56","DOI":"10.12970\/2308-8044.2020.08.07","article-title":"Are drugs containing a carboxylic acid functional group associated with a significant risk of idiosyncratic drug reactions?","volume":"8","author":"Uetrecht","year":"2020","journal-title":"J. Mod. Med. Chem."},{"key":"ref_45","unstructured":"Chen, M., Will, Y., Kang, J., and Casey, D.C. (2018). Causality assessment methods in drug-induced liver injury. Drug-Induced Liver Toxicity, Springer Protocols, Springer Nature. Chapter 27."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s40264-018-0654-2","article-title":"Drug-induced liver injury: Why is the Roussel Uclaf Causality Assessment Method (RUCAM) still used 25 years after its launch?","volume":"41","author":"Danan","year":"2018","journal-title":"Drug Saf."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"853","DOI":"10.3389\/fphar.2019.00853","article-title":"Roussel Uclaf Causality Assessment Method for drug-induced liver injury","volume":"10","author":"Danan","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Danan, G. (2021). Idiosyncratic drug-induced liver injury (DILI) and herb-induced liver injury (HILI): Diagnostic algorithm based on the quantitative Roussel Uclaf Causality Assessment Method (RUCAM). Diagnostics, 11.","DOI":"10.3390\/diagnostics11030458"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/hep.26295","article-title":"Avoiding idiosyncratic DILI: Two is better than one","volume":"58","author":"Kaplowitz","year":"2013","journal-title":"Hepatology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3441\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:32:51Z","timestamp":1760362371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3441"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,26]]},"references-count":49,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22073441"],"URL":"https:\/\/doi.org\/10.3390\/ijms22073441","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,26]]}}}