{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T01:39:28Z","timestamp":1793410768105,"version":"4.5.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"name":"Guizhou Provincial Major Scientific and Technological Program","award":["[2024]015"],"award-info":[{"award-number":["[2024]015"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2026,5]]},"DOI":"10.1007\/s00204-025-04222-w","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T13:16:54Z","timestamp":1770902214000},"page":"1927-1940","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Protein covalent modification and hepatic cytotoxicity of atorvastatin resulting from its metabolic activation"],"prefix":"10.1007","volume":"100","author":[{"given":"Chunjing","family":"Guan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuge","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixia","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8175-1636","authenticated-orcid":false,"given":"Jiang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"issue":"6","key":"4222_CR1","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1002\/jbt.21485","volume":"27","author":"N Abdoli","year":"2013","unstructured":"Abdoli N, Heidari R, Azarmi Y, Eghbal MA (2013) Mechanisms of the statins cytotoxicity in freshly isolated rat hepatocytes. J Biochem Mol Toxicol 27(6):287\u2013294. https:\/\/doi.org\/10.1002\/jbt.21485","journal-title":"J Biochem Mol Toxicol"},{"issue":"3","key":"4222_CR2","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1089\/adt.2022.113","volume":"21","author":"N Agrawal","year":"2023","unstructured":"Agrawal N, Mittal A (2023) High-throughput ultra performance liquid chromatography-tandem mass spectrometry method validation for the estimation of Atorvastatin and active metabolites in human plasma. Assay Drug Dev Technol 21(3):110\u2013125. https:\/\/doi.org\/10.1089\/adt.2022.113","journal-title":"Assay Drug Dev Technol"},{"issue":"8","key":"4222_CR3","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1080\/10937404.2023.2261848","volume":"26","author":"R Allison","year":"2023","unstructured":"Allison R, Guraka A, Shawa IT, Tripathi G, Moritz W, Kermanizadeh A (2023) Drug induced liver injury - a 2023 update. J Toxicol Environ Health B Crit Rev 26(8):442\u2013467. https:\/\/doi.org\/10.1080\/10937404.2023.2261848","journal-title":"J Toxicol Environ Health B Crit Rev"},{"issue":"2","key":"4222_CR4","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1111\/liv.13308","volume":"37","author":"ES Bjornsson","year":"2017","unstructured":"Bjornsson ES (2017) Hepatotoxicity of statins and other lipid-lowering agents. Liver Int 37(2):173\u2013178. https:\/\/doi.org\/10.1111\/liv.13308","journal-title":"Liver Int"},{"key":"4222_CR5","doi-asserted-by":"publisher","DOI":"10.36613\/tgg.1875-6832\/2022.03.03","author":"A Castermans","year":"2022","unstructured":"Castermans A, Hias J, Van der Linden L, Spriet I, Tournoy J (2022) Case of hepatotoxicity of atorvastatin: the search for a possible etiology. Tijdschr Gerontol Geriatr. https:\/\/doi.org\/10.36613\/tgg.1875-6832\/2022.03.03","journal-title":"Tijdschr Gerontol Geriatr"},{"issue":"7","key":"4222_CR6","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1053\/j.gastro.2015.03.006","volume":"148","author":"N Chalasani","year":"2015","unstructured":"Chalasani N, Bonkovsky HL, Fontana R et al (2015) Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology 148(7):1340\u201352.e7. https:\/\/doi.org\/10.1053\/j.gastro.2015.03.006","journal-title":"Gastroenterology"},{"issue":"2","key":"4222_CR7","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2020.100086","volume":"1","author":"M Charni-Natan","year":"2020","unstructured":"Charni-Natan M, Goldstein I (2020) Protocol for primary mouse hepatocyte isolation. STAR Protoc 1(2):100086. https:\/\/doi.org\/10.1016\/j.xpro.2020.100086","journal-title":"STAR Protoc"},{"issue":"10","key":"4222_CR8","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1016\/j.dld.2006.04.013","volume":"38","author":"AT Clarke","year":"2006","unstructured":"Clarke AT, Mills PR (2006) Atorvastatin associated liver disease. Dig Liver Dis 38(10):772\u2013777. https:\/\/doi.org\/10.1016\/j.dld.2006.04.013","journal-title":"Dig Liver Dis"},{"key":"4222_CR9","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-025-03995-4","author":"L Dong","year":"2025","unstructured":"Dong L, Hao X, Liu M et al (2025) Metabolic activation and cytotoxicity of ibudilast mediated by CYP3A4. Arch Toxicol. https:\/\/doi.org\/10.1007\/s00204-025-03995-4","journal-title":"Arch Toxicol"},{"issue":"1","key":"4222_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/03602532.2016.1257021","volume":"49","author":"AA El-Sherbeni","year":"2017","unstructured":"El-Sherbeni AA, El-Kadi AO (2017) Microsomal cytochrome P450 as a target for drug discovery and repurposing. Drug Metab Rev 49(1):1\u201317. https:\/\/doi.org\/10.1080\/03602532.2016.1257021","journal-title":"Drug Metab Rev"},{"key":"4222_CR11","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.jpba.2018.10.045","volume":"164","author":"A El-Zailik","year":"2019","unstructured":"El-Zailik A, Cheung LK, Wang Y, Sherman V, Chow DS (2019) Simultaneous LC-MS\/MS analysis of simvastatin, atorvastatin, rosuvastatin and their active metabolites for plasma samples of obese patients underwent gastric bypass surgery. J Pharm Biomed Anal 164:258\u2013267. https:\/\/doi.org\/10.1016\/j.jpba.2018.10.045","journal-title":"J Pharm Biomed Anal"},{"issue":"3","key":"4222_CR12","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1007\/s40256-016-0205-0","volume":"17","author":"AM Ferreira","year":"2017","unstructured":"Ferreira AM, Marques da Silva P (2017) Defining the place of Ezetimibe\/Atorvastatin in the management of hyperlipidemia. Am J Cardiovasc Drugs 17(3):169\u2013181. https:\/\/doi.org\/10.1007\/s40256-016-0205-0","journal-title":"Am J Cardiovasc Drugs"},{"issue":"10","key":"4222_CR13","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1002\/jat.3825","volume":"39","author":"LZ Li","year":"2019","unstructured":"Li LZ, Zhao ZM, Zhang L et al (2019) Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway. J Appl Toxicol 39(10):1394\u20131404. https:\/\/doi.org\/10.1002\/jat.3825","journal-title":"J Appl Toxicol"},{"issue":"4","key":"4222_CR14","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1021\/acschembio.1c00917","volume":"17","author":"W Li","year":"2022","unstructured":"Li W, Hu Z, Sun C et al (2022) A metabolic activation-based chemoproteomic platform to profile adducted proteins derived from furan-containing compounds. ACS Chem Biol 17(4):873\u2013882. https:\/\/doi.org\/10.1021\/acschembio.1c00917","journal-title":"ACS Chem Biol"},{"issue":"1","key":"4222_CR15","doi-asserted-by":"publisher","DOI":"10.1002\/bmc.5515","volume":"37","author":"W Li","year":"2023","unstructured":"Li W, Xu X, Wang S, Li Y, Zhang Y, Zhang T (2023) Development of a UPLC-MS\/MS method for the simultaneous determination of atorvastatin, 2-hydroxy atorvastatin, and naringenin in rat plasma and its application to pharmacokinetic interaction studies. Biomed Chromatogr 37(1):e5515. https:\/\/doi.org\/10.1002\/bmc.5515","journal-title":"Biomed Chromatogr"},{"key":"4222_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.toxlet.2024.12.009","volume":"404","author":"S Liu","year":"2025","unstructured":"Liu S, Zhao G, Xu Y et al (2025) Metabolic activation and hepatic cytotoxicity of osthole mediated by cytochrome P450 enzymes. Toxicol Lett 404:1\u20138. https:\/\/doi.org\/10.1016\/j.toxlet.2024.12.009","journal-title":"Toxicol Lett"},{"issue":"10454","key":"4222_CR17","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/S0140-6736(24)00693-7","volume":"404","author":"R Maiwall","year":"2024","unstructured":"Maiwall R, Kulkarni AV, Arab JP, Piano S (2024) Acute liver failure. Lancet 404(10454):789\u2013802. https:\/\/doi.org\/10.1016\/S0140-6736(24)00693-7","journal-title":"Lancet"},{"issue":"1","key":"4222_CR18","doi-asserted-by":"publisher","first-page":"38","DOI":"10.2174\/1389450118666170125144557","volume":"19","author":"P Manikandan","year":"2018","unstructured":"Manikandan P, Nagini S (2018) Cytochrome P450 structure, function and clinical significance: a review. Curr Drug Targets 19(1):38\u201354. https:\/\/doi.org\/10.2174\/1389450118666170125144557","journal-title":"Curr Drug Targets"},{"issue":"4","key":"4222_CR19","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1067\/mcp.2000.110537","volume":"68","author":"AL Mazzu","year":"2000","unstructured":"Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P (2000) Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 68(4):391\u2013400. https:\/\/doi.org\/10.1067\/mcp.2000.110537","journal-title":"Clin Pharmacol Ther"},{"key":"4222_CR20","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/978-1-0716-2128-8_7","volume":"2455","author":"R Mendoza","year":"2022","unstructured":"Mendoza R, Banerjee I, Reghupaty SC, Yetirajam R, Manna D, Sarkar D (2022) Isolation and culture of mouse hepatocytes and Kupffer cells (KCs). Methods Mol Biol 2455:73\u201384. https:\/\/doi.org\/10.1007\/978-1-0716-2128-8_7","journal-title":"Methods Mol Biol"},{"issue":"1","key":"4222_CR21","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1021\/tx3003824","volume":"26","author":"LA Peterson","year":"2013","unstructured":"Peterson LA (2013) Reactive metabolites in the biotransformation of molecules containing a furan ring. Chem Res Toxicol 26(1):6\u201325. https:\/\/doi.org\/10.1021\/tx3003824","journal-title":"Chem Res Toxicol"},{"issue":"6","key":"4222_CR22","doi-asserted-by":"publisher","first-page":"2065","DOI":"10.1002\/hep.23937","volume":"52","author":"A Reuben","year":"2010","unstructured":"Reuben A, Koch DG, Lee WM (2010) Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 52(6):2065\u20132076. https:\/\/doi.org\/10.1002\/hep.23937","journal-title":"Hepatology"},{"key":"4222_CR23","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.atherosclerosis.2020.12.023","volume":"320","author":"J Rubino","year":"2021","unstructured":"Rubino J, MacDougall DE, Sterling LR, Hanselman JC, Nicholls SJ (2021) Combination of bempedoic acid, ezetimibe, and atorvastatin in patients with hypercholesterolemia: a randomized clinical trial. Atherosclerosis 320:122\u2013128. https:\/\/doi.org\/10.1016\/j.atherosclerosis.2020.12.023","journal-title":"Atherosclerosis"},{"issue":"13","key":"4222_CR24","doi-asserted-by":"publisher","first-page":"4092","DOI":"10.1021\/acs.jafc.1c08144","volume":"70","author":"J Shi","year":"2022","unstructured":"Shi J, Zhao M, Li K et al (2022) Metabolic activation and cytotoxicity of fungicide carbendazim mediated by CYP1A2. J Agric Food Chem 70(13):4092\u20134101. https:\/\/doi.org\/10.1021\/acs.jafc.1c08144","journal-title":"J Agric Food Chem"},{"issue":"3","key":"4222_CR25","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.1089","volume":"11","author":"E Sverre","year":"2023","unstructured":"Sverre E, Munkhaugen J, Kristiansen O et al (2023) Plasma concentration of atorvastatin metabolites correlates with low\u2010density lipoprotein cholesterol reduction in patients with coronary heart disease. Pharmacol Res Perspect 11(3):e01089. https:\/\/doi.org\/10.1002\/prp2.1089","journal-title":"Pharmacol Res Perspect"},{"issue":"8","key":"4222_CR26","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/j.tibtech.2019.01.001","volume":"37","author":"VB Urlacher","year":"2019","unstructured":"Urlacher VB, Girhard M (2019) Cytochrome P450 monooxygenases in biotechnology and synthetic biology. Trends Biotechnol 37(8):882\u2013897. https:\/\/doi.org\/10.1016\/j.tibtech.2019.01.001","journal-title":"Trends Biotechnol"},{"issue":"9","key":"4222_CR27","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1021\/acs.chemrestox.2c00111","volume":"35","author":"Y Zhao","year":"2022","unstructured":"Zhao Y, Sun C, Su M et al (2022) Evidence for metabolic activation of Omeprazole in vitro and in vivo. Chem Res Toxicol 35(9):1493\u20131502. https:\/\/doi.org\/10.1021\/acs.chemrestox.2c00111","journal-title":"Chem Res Toxicol"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-025-04222-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-025-04222-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-025-04222-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T08:10:04Z","timestamp":1776327004000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-025-04222-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,12]]},"references-count":27,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["4222"],"URL":"https:\/\/doi.org\/10.1007\/s00204-025-04222-w","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,12]]},"assertion":[{"value":"10 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}