{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:40:53Z","timestamp":1793731253893,"version":"4.6.1"},"reference-count":105,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Environmental Toxicology and Pharmacology"],"published-print":{"date-parts":[[2022,10]]},"DOI":"10.1016\/j.etap.2022.103967","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T12:06:49Z","timestamp":1662034009000},"page":"103967","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":83,"special_numbering":"C","title":["Valproic acid induced liver injury: An insight into molecular toxicological mechanism"],"prefix":"10.1016","volume":"95","author":[{"given":"Devaraj","family":"Ezhilarasan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uthirappan","family":"Mani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"2","key":"10.1016\/j.etap.2022.103967_bib1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s40268-014-0042-z","article-title":"Valproate-induced liver injury: modulation by the omega-3 fatty acid DHA proposes a novel anticonvulsant regimen","volume":"14","author":"Abdel-Dayem","year":"2014","journal-title":"Drugs R. D."},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jphs.2020.01.007","article-title":"Ellagic acid attenuates liver toxicity induced by valproic acid in rats","volume":"143","author":"Abdelkader","year":"2020","journal-title":"J. Pharm. Sci."},{"key":"10.1016\/j.etap.2022.103967_bib3","doi-asserted-by":"crossref","first-page":"118","DOI":"10.4103\/jnsm.jnsm_123_20","article-title":"Valporic acid-induced hepatotoxicity in rats: protective effect of selenium","volume":"4","author":"Adikwu","year":"2021","journal-title":"J. Nat. Sci. Med."},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib4","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1007\/s12011-017-0944-z","article-title":"Zinc deficiency and oxidative stress involved in valproic acid induced hepatotoxicity: protection by zinc and selenium supplementation","volume":"179","author":"Ahangar","year":"2017","journal-title":"Biol. Trace Elem. Res."},{"issue":"12","key":"10.1016\/j.etap.2022.103967_bib5","doi-asserted-by":"crossref","DOI":"10.1002\/jbt.22227","article-title":"Agmatine protects against sodium valproate-induced hepatic injury in mice via modulation of nuclear factor-\u03baB\/inducible nitric oxide synthetase pathway","volume":"32","author":"Ahmed","year":"2018","journal-title":"J. Biochem Mol. Toxicol."},{"issue":"5","key":"10.1016\/j.etap.2022.103967_bib6","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.bcp.2009.10.011","article-title":"Inhibition of hepatic carnitine palmitoyl-transferase I (CPT IA) by valproyl-CoA as a possible mechanism of valproate-induced steatosis","volume":"79","author":"Aires","year":"2010","journal-title":"Biochem Pharm."},{"issue":"2","key":"10.1016\/j.etap.2022.103967_bib7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1517\/14740338.4.2.345","article-title":"Teratogenicity of sodium valproate","volume":"4","author":"Alsdorf","year":"2005","journal-title":"Expert Opin. Drug Saf."},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib8","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1124\/dmd.108.022426","article-title":"Effect of aging on glucuronidation of valproic acid in human liver microsomes and the role of UDP-glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10","volume":"37","author":"Argikar","year":"2009","journal-title":"Drug Metab. Dispos."},{"issue":"4","key":"10.1016\/j.etap.2022.103967_bib9","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.cld.2013.07.011","article-title":"Drug-induced liver injury from antiepileptic drugs","volume":"17","author":"Au","year":"2013","journal-title":"Clin. Liver Dis."},{"key":"10.1016\/j.etap.2022.103967_bib10","unstructured":"Bauer L.A. Applied Clinical Pharmacokinetics 3ed. New York: McGraw-Hill Education; 2014."},{"issue":"4","key":"10.1016\/j.etap.2022.103967_bib11","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jhep.2010.11.006","article-title":"Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver","volume":"54","author":"Begriche","year":"2011","journal-title":"J. Hepatol."},{"issue":"10","key":"10.1016\/j.etap.2022.103967_bib12","doi-asserted-by":"crossref","first-page":"3463","DOI":"10.1007\/s00204-020-02835-x","article-title":"Valproic acid promotes mitochondrial dysfunction in primary human hepatocytes in vitro; impact of C\/EBP\u03b1-controlled gene expression","volume":"94","author":"Caiment","year":"2020","journal-title":"Arch. Toxicol."},{"issue":"8","key":"10.1016\/j.etap.2022.103967_bib13","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1080\/15376516.2021.1943089","article-title":"Vitamin U prevents valproic acid-induced liver injury through supporting enzymatic antioxidant system and increasing hepatocyte proliferation triggered by inflammation and apoptosis","volume":"31","author":"Celik","year":"2021","journal-title":"Toxicol. Mech. Methods"},{"issue":"4","key":"10.1016\/j.etap.2022.103967_bib14","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1080\/03602530600959433","article-title":"Oxidative stress as a mechanism of valproic acid-associated hepatotoxicity","volume":"38","author":"Chang","year":"2006","journal-title":"Drug Metab. Rev."},{"key":"10.1016\/j.etap.2022.103967_bib15","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.freeradbiomed.2020.02.025","article-title":"Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease","volume":"152","author":"Chen","year":"2020","journal-title":"Free Radic. Biol. Med"},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib16","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.nmd.2007.11.005","article-title":"155th ENMC workshop: polymerase gamma and disorders of mitochondrial DNA synthesis, 21-23 September 2007, Naarden, The Netherlands","volume":"18","author":"Chinnery","year":"2008","journal-title":"Neuromuscul. Disord."},{"key":"10.1016\/j.etap.2022.103967_bib17","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/0006-2952(90)90560-8","article-title":"Early changes in hepatic redox homeostasis following treatment with a single dose of valproic acid","volume":"40","author":"Cotariu","year":"1990","journal-title":"Biochem Pharm."},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib18","doi-asserted-by":"crossref","first-page":"221","DOI":"10.21608\/ajfm.2013.19412","article-title":"Influence of silymarin on valproic acid induced hepatotoxicity in adult male Albino rats","volume":"20","author":"El-Khateeb","year":"2013","journal-title":"Ain Shams J. Forensic Med. Clin. Toxicol."},{"issue":"7\u20138","key":"10.1016\/j.etap.2022.103967_bib19","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.bbalip.2011.04.014","article-title":"Eicosapentaenoic acid ablates valproate-induced liver oxidative stress and cellular derangement without altering its clearance rate: dynamic synergy and therapeutic utility","volume":"1811","author":"El-Mowafy","year":"2011","journal-title":"Biochim Biophys. Acta"},{"issue":"2","key":"10.1016\/j.etap.2022.103967_bib20","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ajg.2018.03.002","article-title":"Oxidative stress is bane in chronic liver diseases: Clinical and experimental perspective","volume":"19","author":"Ezhilarasan","year":"2018","journal-title":"Arab J. Gastroenterol."},{"issue":"4","key":"10.1016\/j.etap.2022.103967_bib21","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.hbpd.2021.04.010","article-title":"Mitochondria: a critical hub for hepatic stellate cells activation during chronic liver diseases","volume":"20","author":"Ezhilarasan","year":"2021","journal-title":"Hepatobiliary Pancreat. Dis. Int"},{"issue":"04","key":"10.1016\/j.etap.2022.103967_bib22","first-page":"220","article-title":"HAART and hepatotoxicity","volume":"7","author":"Ezhilarasan","year":"2017","journal-title":"J. Appl. Pharm. Sci."},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib23","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/0306-9877(90)90049-K","article-title":"Valproyl CoA: an active metabolite of valproate?","volume":"31","author":"Friel","year":"1990","journal-title":"Med. Hypotheses"},{"issue":"5","key":"10.1016\/j.etap.2022.103967_bib24","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1124\/mol.119.118646","article-title":"Obeticholic acid ameliorates valproic acid-induced hepatic steatosis and oxidative stress","volume":"97","author":"Gai","year":"2020","journal-title":"Mol. Pharm."},{"issue":"5","key":"10.1016\/j.etap.2022.103967_bib25","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1080\/20009666.2018.1514933","article-title":"Valproic acid induced acute liver injury resulting in hepatic encephalopathy- a case report and literature review","volume":"8","author":"Gayam","year":"2018","journal-title":"J. Community Hosp. Intern Med. Perspect."},{"issue":"9","key":"10.1016\/j.etap.2022.103967_bib26","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1002\/tox.23557","article-title":"Syringic acid and silymarin concurrent administration inhibits sodium valproate-induced liver injury in rats","volume":"37","author":"Gheena","year":"2022","journal-title":"Environ. Toxicol ."},{"issue":"4","key":"10.1016\/j.etap.2022.103967_bib27","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1097\/FPC.0b013e32835ea0b2","article-title":"Valproic acid pathway: pharmacokinetics and pharmacodynamics","volume":"23","author":"Ghodke-Puranik","year":"2013","journal-title":"Pharm. Genom."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib28","doi-asserted-by":"crossref","first-page":"e344","DOI":"10.1097\/MJT.0000000000000706","article-title":"Levocarnitine for the treatment of valproic acid-induced hyperammonemic encephalopathy in children: the experience of a large, tertiary care pediatric hospital and a poison center","volume":"26","author":"Glatstein","year":"2019","journal-title":"Am. J. Ther."},{"issue":"6","key":"10.1016\/j.etap.2022.103967_bib29","doi-asserted-by":"crossref","first-page":"395","DOI":"10.2131\/jts.43.395","article-title":"Ether-phosphatidylcholine characterized by consolidated plasma and liver lipidomics is a predictive biomarker for valproic acid-induced hepatic steatosis","volume":"43","author":"Goda","year":"2018","journal-title":"J. Toxicol. Sci."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib30","doi-asserted-by":"crossref","first-page":"343","DOI":"10.2174\/1381612825666190329145428","article-title":"Valproic acid and the liver injury in patients with epilepsy: an update","volume":"25","author":"Guo","year":"2019","journal-title":"Curr. Pharm. Des."},{"issue":"6","key":"10.1016\/j.etap.2022.103967_bib31","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.3390\/cells10061355","article-title":"Epigenetic regulation of peroxisome proliferator-activated receptor gamma mediates high-fat diet-induced non-alcoholic fatty liver disease","volume":"10","author":"Hajri","year":"2021","journal-title":"Cells"},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib32","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1056\/NEJMra1816149","article-title":"Drug-induced liver injury - types and phenotypes","volume":"381","author":"Hoofnagle","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.etap.2022.103967_bib33","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1212\/WNL.34.10.1393","article-title":"Selenium, zinc, and copper changes with valproic acid: possible relation to drug side effects","volume":"34","author":"Hurd","year":"1984","journal-title":"Neurology"},{"issue":"8","key":"10.1016\/j.etap.2022.103967_bib34","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3109\/15376516.2013.821567","article-title":"Toxicity of valproic acid in isolated rat liver mitochondria","volume":"23","author":"Jafarian","year":"2013","journal-title":"Toxicol. Mech. Methods"},{"issue":"6","key":"10.1016\/j.etap.2022.103967_bib35","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.3390\/ijms22062954","article-title":"Idiosyncratic drug-induced liver injury: mechanistic and clinical challenges","volume":"22","author":"Jee","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.etap.2022.103967_bib36","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1527-3458.2003.tb00249.x","article-title":"Valproate: past, present, and future","volume":"9","author":"Johannessen","year":"2003","journal-title":"CNS Drug Rev."},{"issue":"2","key":"10.1016\/j.etap.2022.103967_bib37","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.yexmp.2015.01.003","article-title":"Sodium valproate ameliorates diabetes-induced fibrosis and renal damage by the inhibition of histone deacetylases in diabetic rat","volume":"98","author":"Khan","year":"2015","journal-title":"Exp. Mol. Pathol."},{"issue":"5","key":"10.1016\/j.etap.2022.103967_bib38","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1007\/s11033-021-06428-4","article-title":"Taurine attenuates valproic acid-induced hepatotoxicity via modulation of RIPK1\/RIPK3\/MLKL-mediated necroptosis signaling in mice","volume":"48","author":"Khodayar","year":"2021","journal-title":"Mol. Biol. Rep."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib39","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.taap.2011.03.004","article-title":"Glutathione depletion by valproic acid in sandwich-cultured rat hepatocytes: Role of biotransformation and temporal relationship with onset of toxicity","volume":"252","author":"Kiang","year":"2011","journal-title":"Toxicol. Appl. Pharm."},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib40","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1046\/j.1442-200x.1999.01012.x","article-title":"Influence of valproic acid on the expression of various acyl-CoA dehydrogenases in rats","volume":"41","author":"Kibayashi","year":"1999","journal-title":"Pedia Int."},{"issue":"9","key":"10.1016\/j.etap.2022.103967_bib41","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1038\/cdd.2010.19","article-title":"production triggering apoptosis is directly linked to Romo1 and Bcl-X(L)","volume":"17","author":"Kim","year":"2010","journal-title":"Cell Death Differ."},{"issue":"2","key":"10.1016\/j.etap.2022.103967_bib42","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1124\/jpet.107.131185","article-title":"Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores","volume":"324","author":"Knapp","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"10.1016\/j.etap.2022.103967_bib43","doi-asserted-by":"crossref","DOI":"10.1016\/j.tice.2021.101526","article-title":"Protective effects of naringin on valproic acid-induced hepatotoxicity in rats","volume":"72","author":"Koroglu","year":"2021","journal-title":"Tissue Cell"},{"issue":"7","key":"10.1016\/j.etap.2022.103967_bib44","first-page":"446","volume":"67","author":"Krzy\u015bciak","year":"2010","journal-title":"Przegl Lek."},{"issue":"7","key":"10.1016\/j.etap.2022.103967_bib45","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/S0090-9556(24)15355-X","article-title":"Disposition of valproic acid in maternal, fetal, and newborn sheep. I: placental transfer, plasma protein binding, and clearance","volume":"28","author":"Kumar","year":"2000","journal-title":"Drug Metab. Dispos."},{"issue":"4","key":"10.1016\/j.etap.2022.103967_bib46","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.livres.2018.12.001","article-title":"Hepatic lipid homeostasis by peroxisome proliferator-activated receptor gamma 2","volume":"2","author":"Lee","year":"2018","journal-title":"Liver Res."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib47","first-page":"771","article-title":"RIP1\/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review)","volume":"44","author":"Liu","year":"2019","journal-title":"Int. J. Mol. Med."},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib48","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.eplepsyres.2009.04.004","article-title":"Non-alcoholic fatty liver disease (NAFLD), insulin resistance and lipid profile in antiepileptic drug treatment","volume":"86","author":"Luef","year":"2009","journal-title":"Epilepsy Res"},{"key":"10.1016\/j.etap.2022.103967_bib49","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/ana.20074","article-title":"Valproate therapy and nonalcoholic fatty liver disease","volume":"55","author":"Luef","year":"2004","journal-title":"Ann. Neurol."},{"key":"10.1016\/j.etap.2022.103967_bib50","doi-asserted-by":"crossref","DOI":"10.1016\/j.tox.2020.152585","article-title":"Involvement of CYP2E1-ROS-CD36\/DGAT2 axis in the pathogenesis of VPA-induced hepatic steatosis in vivo and in vitro","volume":"445","author":"Ma","year":"2020","journal-title":"Toxicology"},{"issue":"16","key":"10.1016\/j.etap.2022.103967_bib51","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1056\/NEJMoa0803531","article-title":"NEAD Study Group. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs","volume":"360","author":"Meador","year":"2009","journal-title":"N. Engl. J. Med."},{"issue":"6","key":"10.1016\/j.etap.2022.103967_bib52","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.3390\/jcm10061153","article-title":"Valproic acid-induced liver injury: a case-control study from a prospective pharmacovigilance program in a tertiary hospital","volume":"10","author":"Meseguer","year":"2021","journal-title":"J. Clin. Med."},{"issue":"5","key":"10.1016\/j.etap.2022.103967_bib53","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1111\/bcp.13510","article-title":"A systematic review of population pharmacokinetics of valproic acid","volume":"84","author":"Methaneethorn","year":"2018","journal-title":"Br. J. Clin. Pharm."},{"key":"10.1016\/j.etap.2022.103967_bib54","first-page":"435","article-title":"Pharmacodynamic properties of N-dipropylacetic acid","volume":"18","author":"Meunier","year":"1963","journal-title":"Therapie"},{"key":"10.1016\/j.etap.2022.103967_bib55","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.3389\/fphar.2019.01482","article-title":"Drug-induced liver injury: biomarkers, requirements, candidates, and validation","volume":"10","author":"Meunier","year":"2019","journal-title":"Front Pharm."},{"issue":"5","key":"10.1016\/j.etap.2022.103967_bib56","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1139\/cjpp-2019-0456","article-title":"Antioxidant and anti-inflammatory properties of alpha-lipoic acid protect against valproic acid-induced liver injury","volume":"99","author":"Mohammed","year":"2021","journal-title":"Can. J. Physiol. Pharm."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib57","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/cr.2008.31","article-title":"TNFalpha and reactive oxygen species in necrotic cell death","volume":"18","author":"Morgan","year":"2008","journal-title":"Cell Res."},{"issue":"2","key":"10.1016\/j.etap.2022.103967_bib58","first-page":"63","article-title":"Valproic acid-induced hepatotoxicity and the protective role of thiol reductants","volume":"3","author":"Najafi","year":"2017","journal-title":"Trends Pharm. Sci."},{"issue":"15","key":"10.1016\/j.etap.2022.103967_bib59","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.clinbiochem.2013.06.012","article-title":"Adverse drug reactions induced by valproic acid","volume":"46","author":"Nanau","year":"2013","journal-title":"Clin. Biochem."},{"issue":"8","key":"10.1016\/j.etap.2022.103967_bib60","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1111\/j.1440-1746.2006.04313.x","article-title":"Oxidative stress in experimental liver microvesicular steatosis: role of mitochondria and peroxisomes","volume":"21","author":"Natarajan","year":"2006","journal-title":"J. Gastroenterol. Hepatol."},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib61","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s11033-019-05134-6","article-title":"Melatonin ameliorates sodium valproate-induced hepatotoxicity in rats","volume":"47","author":"Oztopuz","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"10.1016\/j.etap.2022.103967_bib62","doi-asserted-by":"crossref","DOI":"10.3390\/ijms17071020","article-title":"Computational identification of the paralogs and orthologs of human cytochrome P450 superfamily and the implication in drug discovery","volume":"17","author":"Pan","year":"2016","journal-title":"Int J. Mol. Sci."},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib63","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1096\/fj.201900927RR","article-title":"Butyrate prevents valproate-induced liver injury: In vitro and in vivo evidence","volume":"34","author":"Pirozzi","year":"2020","journal-title":"FASEB J."},{"issue":"4","key":"10.1016\/j.etap.2022.103967_bib64","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.tiv.2012.01.020","article-title":"A new approach on valproic acid induced hepatotoxicity: involvement of lysosomal membrane leakiness and cellular proteolysis","volume":"26","author":"Pourahmad","year":"2012","journal-title":"Toxicol. Vitr."},{"key":"10.1016\/j.etap.2022.103967_bib65","unstructured":"Rahman M., Nguyen H. Valproic Acid. [Updated 2021 Oct 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK559112\/."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib66","doi-asserted-by":"crossref","first-page":"102","DOI":"10.3390\/livers1030010","article-title":"Mitochondrial dynamics in drug-induced liver injury","volume":"1","author":"Ramachandran","year":"2021","journal-title":"Livers"},{"key":"10.1016\/j.etap.2022.103967_bib67","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1002\/hep.23937","article-title":"Druginduced acute liver failure: results of a U.S. multicenter, prospective study","volume":"52","author":"Reuben","year":"2010","journal-title":"Hepatology"},{"issue":"1","key":"10.1016\/j.etap.2022.103967_bib68","doi-asserted-by":"crossref","first-page":"11785","DOI":"10.1038\/s41598-020-68725-5","article-title":"Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae","volume":"10","author":"Salsaa","year":"2020","journal-title":"Sci. Rep."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib69","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.seizure.2010.01.002","article-title":"POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders","volume":"19","author":"Saneto","year":"2010","journal-title":"Seizure"},{"issue":"2","key":"10.1016\/j.etap.2022.103967_bib70","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3109\/15376516.2015.1128034","article-title":"High-calorie diet inflates steatogenic effects of valproic acid in mice","volume":"26","author":"Sathiya Priya","year":"2016","journal-title":"Toxicol. Mech. Methods"},{"issue":"2\u20133","key":"10.1016\/j.etap.2022.103967_bib71","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.tox.2005.10.004","article-title":"Valproic acid monotherapy induces DNA oxidative damage","volume":"217","author":"Schulpis","year":"2006","journal-title":"Toxicology"},{"issue":"4","key":"10.1016\/j.etap.2022.103967_bib72","doi-asserted-by":"crossref","first-page":"G583","DOI":"10.1152\/ajpgi.00422.2005","article-title":"Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways","volume":"290","author":"Schwabe","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"issue":"6","key":"10.1016\/j.etap.2022.103967_bib73","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/j.1600-0773.1999.tb02025.x","article-title":"Effect of acute and chronic administration of sodium valproate on lipid peroxidation and antioxidant system in rat liver","volume":"85","author":"Se\u00e7kin","year":"1999","journal-title":"Pharm. Toxicol."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib74","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s00109-015-1358-z","article-title":"Valproic acid suppresses collagen by selective regulation of Smads in conjunctival fibrosis","volume":"94","author":"Seet","year":"2016","journal-title":"J. Mol. Med."},{"key":"10.1016\/j.etap.2022.103967_bib75","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/j.1528-1157.1993.tb02419.x","article-title":"metabolites in various clinical conditions of probable VPA associated hepatotoxicity","volume":"34","author":"Siemes","year":"1993","journal-title":"Epilepsia"},{"issue":"5","key":"10.1016\/j.etap.2022.103967_bib76","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1111\/bcpt.13190","article-title":"A role of peroxisome proliferator-activated receptor \u03b3 in non-alcoholic fatty liver disease","volume":"124","author":"Skat-R\u00f8rdam","year":"2019","journal-title":"Basic Clin. Pharm. Toxicol."},{"issue":"10","key":"10.1016\/j.etap.2022.103967_bib77","doi-asserted-by":"crossref","first-page":"3562","DOI":"10.1016\/j.fct.2012.07.056","article-title":"Effects of vitamin U (S-methyl methionine sulphonium chloride) on valproic acid induced liver injury in rats","volume":"50","author":"Sokmen","year":"2012","journal-title":"Food Chem. Toxicol."},{"issue":"10","key":"10.1016\/j.etap.2022.103967_bib78","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1111\/febs.15122","article-title":"Valproic acid targets HDAC1\/2 and HDAC1\/PTEN\/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer","volume":"287","author":"Sun","year":"2020","journal-title":"FEBS J."},{"issue":"11","key":"10.1016\/j.etap.2022.103967_bib79","first-page":"1169","article-title":"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."},{"issue":"8","key":"10.1016\/j.etap.2022.103967_bib80","doi-asserted-by":"crossref","first-page":"730","DOI":"10.21037\/atm-2020-ubih-05","article-title":"Mechanism of idiosyncratic drug induced liver injury (DILI): unresolved basic issues","volume":"9","author":"Teschke","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"10.1016\/j.etap.2022.103967_bib81","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.dnarep.2017.08.002","article-title":"Valproic acid sensitizes breast cancer cells to hydroxyurea through inhibiting RPA2 hyperphosphorylation-mediated DNA repair pathway","volume":"58","author":"Tian","year":"2017","journal-title":"DNA Repair"},{"key":"10.1016\/j.etap.2022.103967_bib82","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1016\/S0891-5849(03)00151-5","article-title":"The effect of valproic acid on hepatic and plasma levels of 15-F2t-isoprostane in rats","volume":"34","author":"Tong","year":"2003","journal-title":"Free Radic. Biol. Med"},{"issue":"11","key":"10.1016\/j.etap.2022.103967_bib83","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1016\/j.freeradbiomed.2005.02.007","article-title":"Valproic acid glucuronidation is associated with increases in 15-F2t-isoprostane in rats","volume":"38","author":"Tong","year":"2005","journal-title":"Free Radic. Biol. Med"},{"key":"10.1016\/j.etap.2022.103967_bib84","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1093\/toxsci\/kfi184","article-title":"Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats","volume":"86","author":"Tong","year":"2005","journal-title":"Toxicol. Sci."},{"key":"10.1016\/j.etap.2022.103967_bib85","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1093\/toxsci\/kfi185","article-title":"Valproic acid II: effects on oxidative stress, mitochondrial membrane potential, and cytotoxicity in glutathione-depleted rat hepatocytes","volume":"86","author":"Tong","year":"2005","journal-title":"Toxicol. Sci."},{"key":"10.1016\/j.etap.2022.103967_bib86","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.tox.2017.11.013","article-title":"Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction","volume":"393","author":"van Breda","year":"2018","journal-title":"Toxicology"},{"issue":"11","key":"10.1016\/j.etap.2022.103967_bib87","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1007\/s00431-009-0927-y","article-title":"Nonalcoholic fatty liver disease during valproate therapy","volume":"168","author":"Verrotti","year":"2009","journal-title":"Eur. J. Pediatr."},{"key":"10.1016\/j.etap.2022.103967_bib88","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1111\/j.1572-0241.2006.01019.x","article-title":"Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States?","volume":"102","author":"Vuppalanchi","year":"2007","journal-title":"Am. J. Gastroenterol."},{"key":"10.1016\/j.etap.2022.103967_bib89","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1111\/j.1365-2796.2007.01818.x","article-title":"Acute liver failure in Sweden: etiology and outcome","volume":"262","author":"Wei","year":"2007","journal-title":"J. Intern Med"},{"key":"10.1016\/j.etap.2022.103967_bib90","unstructured":"Winter M.E. Basic Clinical Pharmacokinetics: 5th ed. Philadelphia: Lippincott Williams & Wilkins Health; 2010."},{"issue":"6","key":"10.1016\/j.etap.2022.103967_bib91","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1111\/j.1528-1167.2008.01877.x","article-title":"Status epilepticus in children with Alpers' disease caused by POLG1 mutations: EEG and MRI features","volume":"50","author":"Wolf","year":"2009","journal-title":"Epilepsia"},{"issue":"10","key":"10.1016\/j.etap.2022.103967_bib92","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1021\/acs.chemrestox.7b00171","article-title":"Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes","volume":"30","author":"Wolters","year":"2017","journal-title":"Chem. Res Toxicol."},{"key":"10.1016\/j.etap.2022.103967_bib93","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxlet.2018.02.026","article-title":"Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes","volume":"289","author":"Wolters","year":"2018","journal-title":"Toxicol. Lett."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib94","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3390\/brainsci10030187","article-title":"Valproic acid-induced hyperammonemic encephalopathy in a patient with bipolar disorder: a case report","volume":"10","author":"Wu","year":"2020","journal-title":"Brain Sci."},{"key":"10.1016\/j.etap.2022.103967_bib95","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1001\/archinte.165.12.1363","article-title":"Adverse drug event surveillance and drug withdrawals in the United States, 1969\u20132002: the importance of reporting suspected reactions","volume":"165","author":"Wysowski","year":"2005","journal-title":"Arch. Intern Med."},{"key":"10.1016\/j.etap.2022.103967_bib96","doi-asserted-by":"crossref","first-page":"819","DOI":"10.3389\/fphar.2019.00819","article-title":"Lipidomic profiling reveals disruption of lipid metabolism in valproic acid-induced hepatotoxicity","volume":"10","author":"Xu","year":"2019","journal-title":"Front. Pharm."},{"issue":"5","key":"10.1016\/j.etap.2022.103967_bib97","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.3892\/ijo.2015.2924","article-title":"Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells","volume":"46","author":"Yamanegi","year":"2015","journal-title":"Int J. Oncol."},{"issue":"4","key":"10.1016\/j.etap.2022.103967_bib98","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1111\/fcp.12608","article-title":"Valproic acid reverses sorafenib resistance through inhibiting activated Notch\/Akt signaling pathway in hepatocellular carcinoma","volume":"35","author":"Yang","year":"2021","journal-title":"Fundam. Clin. Pharm."},{"key":"10.1016\/j.etap.2022.103967_bib99","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev-pharmtox-030220-015007","article-title":"Models of idiosyncratic drug-induced liver injury","volume":"61","author":"Yokoi","year":"2021","journal-title":"Annu. Rev. Pharm. Toxicol."},{"issue":"6","key":"10.1016\/j.etap.2022.103967_bib100","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2165\/00003088-198815060-00002","article-title":"Clinical pharmacokinetics of valproic acid--1988","volume":"15","author":"Zaccara","year":"1988","journal-title":"Clin. Pharm."},{"issue":"10","key":"10.1016\/j.etap.2022.103967_bib101","doi-asserted-by":"crossref","first-page":"6949","DOI":"10.1007\/s11033-021-06674-6","article-title":"Mitochondrial stress response in drug-induced liver injury","volume":"48","author":"Zheng","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"10.1016\/j.etap.2022.103967_bib102","doi-asserted-by":"crossref","DOI":"10.1016\/j.taap.2019.114829","article-title":"Ginsenoside compound K alleviates sodium valproate-induced hepatotoxicity in rats via antioxidant effect, regulation of peroxisome pathway and iron homeostasis","volume":"386","author":"Zhou","year":"2020","journal-title":"Toxicol. Appl. Pharm."},{"issue":"3","key":"10.1016\/j.etap.2022.103967_bib103","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1080\/00498254.2019.1618510","article-title":"Metabolomics reveals the effect of valproic acid on MCF-7 and MDA-MB-231 cells","volume":"50","author":"Zhou","year":"2020","journal-title":"Xenobiotica"},{"issue":"5","key":"10.1016\/j.etap.2022.103967_bib104","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3390\/antiox7050066","article-title":"Selenium-dependent antioxidant enzymes: actions and properties of selenoproteins","volume":"7","author":"Zoidis","year":"2018","journal-title":"Antioxidants"},{"issue":"1\u20133","key":"10.1016\/j.etap.2022.103967_bib105","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1385\/BTER:114:1:41","article-title":"Levels of selenium, zinc, copper, and antioxidant enzyme activity in patients with leukemia","volume":"114","author":"Zuo","year":"2006","journal-title":"Biol. Trace Elem. Res."}],"container-title":["Environmental Toxicology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1382668922001600?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1382668922001600?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T09:51:49Z","timestamp":1761299509000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1382668922001600"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10]]},"references-count":105,"alternative-id":["S1382668922001600"],"URL":"https:\/\/doi.org\/10.1016\/j.etap.2022.103967","relation":{},"ISSN":["1382-6689"],"issn-type":[{"value":"1382-6689","type":"print"}],"subject":[],"published":{"date-parts":[[2022,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Valproic acid induced liver injury: An insight into molecular toxicological mechanism","name":"articletitle","label":"Article Title"},{"value":"Environmental Toxicology and Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.etap.2022.103967","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2022 Elsevier B.V. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"103967"}}