{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:16:42Z","timestamp":1792019802186,"version":"4.4.0"},"reference-count":168,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"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>CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.<\/jats:p>","DOI":"10.3390\/ijms22158221","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T12:59:24Z","timestamp":1627649964000},"page":"8221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":224,"title":["CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1583-0379","authenticated-orcid":false,"given":"Riina","family":"Harjum\u00e4ki","sequence":"first","affiliation":[{"name":"Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"},{"name":"Biopharmaceutics Group, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 07900 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4414-8544","authenticated-orcid":false,"given":"Chris S.","family":"Pridgeon","sequence":"additional","affiliation":[{"name":"Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Ingelman-Sundberg","sequence":"additional","affiliation":[{"name":"Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/0006-2952(84)90466-0","article-title":"Ethanol metabolism in vivo by the microsomal ethanol-oxidizing system in deermice lacking alcohol dehydrogenase (ADH)","volume":"33","author":"Shigeta","year":"1984","journal-title":"Biochem. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7397","DOI":"10.1016\/S0021-9258(19)40958-7","article-title":"Hepatic microsomal alcohol-oxidizing system. Affinity for methanol, ethanol, propanol, and butanol","volume":"250","author":"Teschke","year":"1975","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/0006-2952(81)90131-3","article-title":"Changes in the rat hepatic mixed function oxidase system associated with chronic ethanol vapor inhalation","volume":"30","author":"Morgan","year":"1981","journal-title":"Biochem. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6321","DOI":"10.1016\/S0021-9258(19)69165-9","article-title":"The mechanism of cytochrome P-450-dependent oxidation of ethanol in reconstituted membrane vesicles","volume":"256","author":"Johansson","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1042\/bj2100107","article-title":"Inhibition of microsomal oxidation of alcohols and of hydroxyl-radical-scavenging agents by the iron-chelating agent desferrioxamine","volume":"210","author":"Dicker","year":"1983","journal-title":"Biochem. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/0006-2952(81)90004-6","article-title":"Hepatic microsomal ethanol oxidizing system (MEOS): Respective roles of ethanol and carbohydrates for the enhanced activity after chronic alcohol consumption","volume":"30","author":"Teschke","year":"1981","journal-title":"Biochem. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8472","DOI":"10.1016\/S0021-9258(18)34356-4","article-title":"Purification and characterization of a unique isozyme of cytochrome P-450 from liver microsomes of ethanol-treated rabbits","volume":"257","author":"Koop","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"673","DOI":"10.3109\/00498258209038943","article-title":"On the significance of the cytochrome P-450-dependent hydroxyl radical-mediated oxygenation mechanism","volume":"12","author":"Hagbjork","year":"1982","journal-title":"Xenobiotica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1073\/pnas.84.3.638","article-title":"cDNA and derived amino acid sequence of ethanol-inducible rabbit liver cytochrome P-450 isozyme 3a (P-450ALC)","volume":"84","author":"Khani","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/dna.1991.10.1","article-title":"The P450 Superfamily: Update on New Sequences, Gene Mapping, and Recommended Nomenclature","volume":"10","author":"Nebert","year":"1991","journal-title":"DNA Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9006","DOI":"10.1021\/bi00425a019","article-title":"Human ethanol-inducible P450IIE1: Complete gene sequence, promoter characterization, chromosome mapping, and cDNA-directed expression","volume":"27","author":"Umeno","year":"1988","journal-title":"Biochemistry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1002\/cpt.1275","article-title":"The PharmVar Steering Committee The Evolution of PharmVar","volume":"105","author":"Gaedigk","year":"2019","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1046\/j.1365-2710.2000.00282.x","article-title":"Cytochrome P450 2E1: Its clinical and toxicological role","volume":"25","author":"Tanaka","year":"2000","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_14","first-page":"211","article-title":"The CYP2E subfamily","volume":"450","author":"Ronis","year":"1996","journal-title":"Cytochromes P"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ma, H., Chen, S., I Zheng, K., Yu, Y., Wang, X., Tang, L., Li, G., Rios, R.S., Huang, O., and Zheng, X. (2021). TA allele of rs2070673 in the CYP2E1 gene is associated with lobular inflammation and nonalcoholic steatohepatitis in patients with biopsy-proven nonalcoholic fatty liver disease. J. Gastroenterol. Hepatol.","DOI":"10.1111\/jgh.15554"},{"key":"ref_16","first-page":"1072","article-title":"Identification and induction of cytochrome P450 2E1 in rat Kupffer cells","volume":"258","author":"Koop","year":"1991","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/j.1530-0277.1996.tb01631.x","article-title":"Induction of Cytochrome P-4502E1 by Ethanol in Rat Kupffer Cells","volume":"20","author":"Koivisto","year":"1996","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1111\/hepr.12063","article-title":"Cytochrome P4502E1 inhibitor, chlormethiazole, decreases lipopolysaccharide-induced inflammation in rat Kupffer cells with ethanol treatment","volume":"43","author":"Ye","year":"2013","journal-title":"Hepatol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"17130","DOI":"10.1074\/jbc.M000957200","article-title":"Molecular Basis for the Transport of Cytochrome P450 2E1 to the Plasma Membrane","volume":"275","author":"Neve","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0014-5793(99)01361-7","article-title":"A soluble NH2-terminally truncated catalytically active form of rat cytochrome P450 2E1 targeted to liver mitochondria","volume":"460","author":"Neve","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1152\/physrev.1997.77.2.517","article-title":"Cytochrome P-4502E1: Its physiological and pathological role","volume":"77","author":"Lieber","year":"1997","journal-title":"Physiol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1002\/hep.1840110521","article-title":"Presence of functional cytochrome P-450 on isolated rat hepatocyte plasma membrane","volume":"11","author":"Loeper","year":"1990","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0016-5085(93)90853-5","article-title":"Cytochromes P-450 in human hepatocyte plasma membrane: Recognition by several autoantibodies","volume":"104","author":"Loeper","year":"1993","journal-title":"Gastroenterology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1006\/abbi.1996.0415","article-title":"Enzyme-Specific Transport of Rat Liver Cytochrome P450 to the Golgi Apparatus","volume":"333","author":"Neve","year":"1996","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1096\/fasebj.6.2.1537462","article-title":"Oxidative and reductive metabolism by cytochrome P450 2E1","volume":"6","author":"Koop","year":"1992","journal-title":"FASEB J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"101470","DOI":"10.1016\/j.clinre.2020.05.018","article-title":"Cytochrome P450 2E1 should not be neglected for acetaminophen-induced liver injury in metabolic diseases with altered insulin levels or glucose homeostasis","volume":"45","author":"Massart","year":"2021","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Seitz, H.K. (2020). The role of cytochrome P4502E1 in the pathogenesis of alcoholic liver disease and carcinogenesis. Chem. Interact., 316.","DOI":"10.1016\/j.cbi.2019.108918"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/978-3-319-09614-8_4","article-title":"Alcohol and Cancer: An Overview with Special Emphasis on the Role of Acetaldehyde and Cytochrome P450 2E1","volume":"815","author":"Seitz","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0014-5793(86)80214-9","article-title":"Hydroxylation of acetone by ethanol- and acetone-inducible cytochrome P-450 in liver microsomes and reconstituted membranes","volume":"196","author":"Johansson","year":"1986","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"138a","DOI":"10.1111\/j.1530-0277.1996.tb01764.x","article-title":"Ethanol-Inducible Cytochrome P450 (CYP2E1): Biochemistry, Molecular Biology and Clinical Relevance: 1996 Update","volume":"20","author":"Song","year":"1996","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.mrfmmm.2004.04.021","article-title":"Role of cytochromes P450 in chemical toxicity and oxidative stress: Studies with CYP2E1","volume":"569","author":"Gonzalez","year":"2005","journal-title":"Mutat. Res. Mol. Mech. Mutagen."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Correia, M.A., and Kwon, D. (2020). Why Hepatic CYP2E1-Elevation by Itself Is Insufficient for Inciting NAFLD\/NASH: Inferences from Two Genetic Knockout Mouse Models. Biology, 9.","DOI":"10.3390\/biology9120419"},{"key":"ref_33","first-page":"914","article-title":"Inhibition of CYP2E1 Activity does not Abolish Pulsatile Urine Alcohol Concentrations During Chronic Alcohol Infusions","volume":"230","author":"Badger","year":"1995","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"33698","DOI":"10.1074\/jbc.M805999200","article-title":"Structures of Human Cytochrome P-450 2E1","volume":"283","author":"Porubsky","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"22282","DOI":"10.1074\/jbc.M110.109017","article-title":"Human Cytochrome P450 2E1 Structures with Fatty Acid Analogs Reveal a Previously Unobserved Binding Mode","volume":"285","author":"Porubsky","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4065","DOI":"10.1073\/pnas.82.12.4065","article-title":"Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: Ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid","volume":"82","author":"Koop","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/bies.950120906","article-title":"Multiple mechanisms in the regulation of ethanol-inducible cytochrome P450IIE1","volume":"12","author":"Koop","year":"1990","journal-title":"BioEssays"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1210\/mend-1-8-542","article-title":"Stabilization of Cytochrome P450j Messenger Ribonucleic Acid in the Diabetic Rat","volume":"1","author":"Song","year":"1987","journal-title":"Mol. Endocrinol."},{"key":"ref_39","first-page":"474","article-title":"Pretranslational activation of cytochrome P450IIE during ketosis induced by a high fat diet","volume":"41","author":"Yun","year":"1992","journal-title":"Mol. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/BF02975435","article-title":"The alcohol-inducible form of cytochrome P450 (CYP2E1): Role in toxicology and regulation of expression","volume":"23","author":"Novak","year":"2000","journal-title":"Arch. Pharml. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0006-291X(05)81061-7","article-title":"Transcriptional control of CYP2E1 in the perivenous liver region and during starvation","volume":"173","author":"Johansson","year":"1990","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","first-page":"15","article-title":"Targeted CYP2E1 quantification and its correlation to currently acceptable clinical biochemical indices","volume":"23","author":"Yap","year":"2016","journal-title":"J. Biol. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12063","DOI":"10.1074\/jbc.271.20.12063","article-title":"Role of CYP2E1 in the Hepatotoxicity of Acetaminophen","volume":"271","author":"Lee","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1021\/bi00406a019","article-title":"Ethanol-, fasting-, and aceton-inducible cytochromes P-450 in rat liver: Regulation and characteristics of enzymes belonging to the IIB and IIE gene subfamilies","volume":"27","author":"Johansson","year":"1988","journal-title":"Biochemistry"},{"key":"ref_45","first-page":"494","article-title":"Purification of liver microsomal cytochrome P-450 isozymes 3a and 6 from imidazole-treated rabbits. Evidence for the identity of isozyme 3a with the form obtained by ethanol treatment","volume":"25","author":"Koop","year":"1984","journal-title":"Mol. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16689","DOI":"10.1016\/S0021-9258(18)66620-7","article-title":"Complementary DNA and protein sequences of ethanol-inducible rat and human cytochrome P-450s. Transcriptional and post-transcriptional regulation of the rat enzyme","volume":"261","author":"Song","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1073\/pnas.87.8.3225","article-title":"Substrate-, hormone-, and cAMP-regulated cytochrome P450 degradation","volume":"87","author":"Eliasson","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15765","DOI":"10.1016\/S0021-9258(19)49601-4","article-title":"Hormone- and substrate-regulated intracellular degradation of cytochrome P450 (2E1) involving MgATP-activated rapid proteolysis in the endoplasmic reticulum membranes","volume":"267","author":"Eliasson","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.freeradbiomed.2007.11.004","article-title":"CYP2E1 and oxidative liver injury by alcohol","volume":"44","author":"Lu","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9443","DOI":"10.1074\/jbc.M110.176685","article-title":"Ubiquitin-dependent Proteasomal Degradation of Human Liver Cytochrome P450 2E1","volume":"286","author":"Wang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_51","first-page":"383","article-title":"Acetone-regulated synthesis and degradation of cytochrome P4502E2 and cytochrome P4502B1 in rat liver","volume":"198","author":"Ronis","year":"1991","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"25187","DOI":"10.1038\/srep25187","article-title":"Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease","volume":"6","author":"Bell","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_53","unstructured":"Owen, O.E., Patel, M.S., Block, B.S.B., Kreulen, T.H., Reichle, F.A., and Mozzoli, M.A. (1976). Gluconeogenesis in normal, cirrhotic, and diabetic humans. Gluconeogenesis: Its Regulation in Mammalian Species, Wiley."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6447","DOI":"10.1016\/S0021-9258(20)82163-2","article-title":"Mechanisms of hydroxyl radical formation and ethanol oxidation by ethanol-inducible and other forms of rabbit liver microsomal cytochromes P-450","volume":"259","author":"Johansson","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3698","DOI":"10.1021\/bi00557a010","article-title":"Role of hydroxyl radicals in the iron-ethylenediaminetetraacetic acid mediated stimulation of microsomal oxidation of ethanol","volume":"19","author":"Cederbaum","year":"1980","journal-title":"Biochemistry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/0014-5793(85)80790-0","article-title":"Carbon tetrachloride-induced lipid peroxidation dependent on an ethanol-inducible form of rabbit liver microsomal cytochrome P-450","volume":"183","author":"Johansson","year":"1985","journal-title":"FEBS Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e20153","DOI":"10.5812\/ircmj.20153","article-title":"Hepatotoxicity of Halogenated Inhalational Anesthetics","volume":"16","author":"Safari","year":"2014","journal-title":"Iran. Red Crescent Med. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1034\/j.1399-6576.2003.00126.x","article-title":"Concordance between trifluoroacetic acid and hepatic protein trifluoroacetylation after disulfiram inhibition of halothane metabolism in rats","volume":"47","author":"Spracklin","year":"2003","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1053\/gast.1996.v111.pm8698201","article-title":"Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics","volume":"111","author":"Clot","year":"1996","journal-title":"Gastroenterology"},{"key":"ref_60","first-page":"400","article-title":"Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro","volume":"281","author":"Spracklin","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/S0140-6736(96)91011-9","article-title":"Identification of the enzyme responsible for oxidative halothane metabolism: Implications for prevention of halothane hepatitis","volume":"347","author":"Kharasch","year":"1996","journal-title":"Lancet"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/labinvest.2011.193","article-title":"Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver","volume":"92","author":"Knockaert","year":"2011","journal-title":"Lab. Investig."},{"key":"ref_63","first-page":"209","article-title":"The epidemiology of alcoholic liver disease","volume":"27","author":"Mann","year":"2003","journal-title":"Alcohol Res. Health"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"30","DOI":"10.2133\/dmpk.DMPK-10-RV-087","article-title":"Progression of Alcoholic and Non-alcoholic Steatohepatitis: Common Metabolic Aspects of Innate Immune System and Oxidative Stress","volume":"26","author":"Sakaguchi","year":"2011","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.jhep.2012.08.018","article-title":"CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease","volume":"58","author":"Leung","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_66","first-page":"G1135","article-title":"Cytochrome P-450 enzymes and oxidative stress","volume":"281","author":"Robertson","year":"2001","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/0006-2952(89)90338-9","article-title":"Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1)","volume":"38","year":"1989","journal-title":"Biochem. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/0741-8329(93)90063-T","article-title":"Ethanol-inducible cytochrome P4502E1: Genetic polymorphism, regulation, and possible role in the etiology of alcohol-induced liver disease","volume":"10","author":"Johansson","year":"1993","journal-title":"Alcohol"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1042\/bj3400453","article-title":"Relationship between cytochrome P450 catalytic cycling and stability: Fast degradation of ethanol-inducible cytochrome P450 2E1 (CYP2E1) in hepatoma cells is abolished by inactivation of its electron donor NADPH\u2013cytochrome P450 reductase","volume":"340","author":"Zhukov","year":"1999","journal-title":"Biochem. J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"29643","DOI":"10.1074\/jbc.272.47.29643","article-title":"Oxidation Kinetics of Ethanol by Human Cytochrome P450 2E1","volume":"272","author":"Bell","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6812","DOI":"10.1016\/S0021-9258(17)39800-9","article-title":"On the stoichiometry of the oxidase and monooxygenase reactions catalyzed by liver microsomal cytochrome P-450. Products of oxygen reduction","volume":"259","author":"Gorsky","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1053\/jhep.2002.33720","article-title":"Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage","volume":"36","author":"Morgan","year":"2002","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.jhep.2008.10.020","article-title":"The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model","volume":"50","author":"Butura","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.freeradbiomed.2015.12.016","article-title":"Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress","volume":"91","author":"Abdelmegeed","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_75","first-page":"1286","article-title":"Chlormethiazole as an efficient inhibitor of cytochrome P450 2E1 expression in rat liver","volume":"269","author":"Hu","year":"1994","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_76","first-page":"302","article-title":"Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole","volume":"224","author":"Gouillon","year":"2000","journal-title":"Proc. Soc. Exp. Boil. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/hep.510230121","article-title":"Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol","volume":"23","author":"Albano","year":"1996","journal-title":"Hepatology"},{"key":"ref_78","first-page":"1610","article-title":"Modulation of experimental alcohol-induced liver disease by cytochrome P450 2E1 inhibitors","volume":"21","author":"Morimoto","year":"1995","journal-title":"Hepatology"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Seitz, H., and Neuman, M. (2021). The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology. J. Clin. Med., 10.","DOI":"10.3390\/jcm10040858"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Ballway, J., and Song, B.-J. (2021). Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease. Antioxidants, 10.","DOI":"10.3390\/antiox10030384"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.freeradbiomed.2013.09.009","article-title":"CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis","volume":"65","author":"Abdelmegeed","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"207","DOI":"10.2174\/1874467208666150817111114","article-title":"Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances","volume":"10","author":"Abdelmegeed","year":"2017","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1111\/j.1530-0277.2009.00946.x","article-title":"Nitric Oxide-Mediated Intestinal Injury Is Required for Alcohol-Induced Gut Leakiness and Liver Damage","volume":"33","author":"Tang","year":"2009","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_84","first-page":"G185","article-title":"Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability","volume":"305","author":"Forsyth","year":"2013","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0022-2143(03)00140-9","article-title":"Alcoholic liver disease: Is it an \u201cextraintestinal\u201d complication of alcohol-induced intestinal injury?","volume":"142","author":"Keshavarzian","year":"2003","journal-title":"J. Lab. Clin. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/j.1530-0277.2000.tb04629.x","article-title":"Effect of Acute Ethanol Administration on the Intestinal Absorption of Endotoxin in Rats","volume":"24","author":"Tamai","year":"2000","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S0168-8278(87)80003-X","article-title":"Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess","volume":"4","author":"Bode","year":"1987","journal-title":"J. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1053\/jhep.2000.19621","article-title":"Exacerbation of Alcoholic Liver Injury by Enteral Endotoxin in Rats","volume":"32","author":"Mathurin","year":"2000","journal-title":"Hepatology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S0016-5085(98)70211-2","article-title":"Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin","volume":"115","author":"Enomoto","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.jcmgh.2015.01.001","article-title":"Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability","volume":"1","author":"Luther","year":"2015","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3350\/cmh.2020.0129","article-title":"The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease","volume":"27","author":"Jennison","year":"2021","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/j.jhep.2011.02.035","article-title":"DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH","volume":"55","author":"Dostert","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_93","first-page":"179","article-title":"Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity","volume":"482","author":"Elinav","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_94","first-page":"434","article-title":"Nonalcoholic steatohepatitis. Mayo Clinic experiences with a hitherto un-named disease","volume":"55","author":"Ludwig","year":"1980","journal-title":"Mayo Clin. Proc."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1007\/s00125-005-1682-x","article-title":"Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechanisms","volume":"48","author":"Bugianesi","year":"2005","journal-title":"Diabetologia"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1002\/hep.23280","article-title":"Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications","volume":"51","author":"Fabbrini","year":"2010","journal-title":"Hepatology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/hep.21727","article-title":"Metabolic correlates of nonalcoholic fatty liver in women and men","volume":"46","author":"Vega","year":"2007","journal-title":"Hepatology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1053\/gast.2001.23256","article-title":"Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities","volume":"120","author":"Sanyal","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"7006","DOI":"10.3748\/wjg.v22.i31.7006","article-title":"Metabolic aspects of adult patients with nonalcoholic fatty liver disease","volume":"22","author":"Abenavoli","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"148","DOI":"10.2174\/1574887109666141216103908","article-title":"Common features of the metabolic syndrome and nonalcoholic fatty liver disease","volume":"9","author":"Uribe","year":"2015","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"International Consensus Panel. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease","volume":"158","author":"Eslam","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1053\/j.gastro.2020.03.049","article-title":"Risk Factors for Cirrhosis in Contemporary Hepatology Practices\u2014Findings From the Texas Hepatocellular Carcinoma Consortium Cohort","volume":"159","author":"Kanwal","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Bianco, C., Casirati, E., Malvestiti, F., and Valenti, L. (2021). Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets. JHEP Rep., 3.","DOI":"10.1016\/j.jhepr.2021.100284"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s00018-018-2947-0","article-title":"Molecular pathways of nonalcoholic fatty liver disease development and progression","volume":"76","author":"Bessone","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/9547613","article-title":"Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease","volume":"2018","author":"Masarone","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1172\/JCI19197","article-title":"Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production","volume":"113","author":"Pan","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1016\/S0016-5085(96)70028-8","article-title":"Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation","volume":"111","author":"Weltman","year":"1996","journal-title":"Gastroenterology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1111\/j.1572-0241.1999.01377.x","article-title":"Nonalcoholic Steatohepatitis: A Proposal for Grading and Staging The Histological Lesions","volume":"94","author":"Brunt","year":"1999","journal-title":"Am. J. Gastroenterol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/hep.510270121","article-title":"Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis","volume":"27","author":"Weltman","year":"1998","journal-title":"Hepatology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.clinre.2011.04.015","article-title":"Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: Mechanisms and pathophysiological role","volume":"35","author":"Aubert","year":"2011","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1042\/CS20030285","article-title":"Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients","volume":"106","author":"Videla","year":"2004","journal-title":"Clin. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1006\/abbi.1996.9785","article-title":"Effects of Fatty Acids and Ketone Bodies on Cytochromes P450 2B, 4A, and 2E1 Expression in Primary Cultured Rat Hepatocytes","volume":"337","author":"Zangar","year":"1997","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0009-2797(97)00075-6","article-title":"Insulin effects on CYP2E1, 2B, 3A, and 4A expression in primary cultured rat hepatocytes","volume":"107","author":"Woodcroft","year":"1997","journal-title":"Chem. Interact."},{"key":"ref_116","first-page":"E532","article-title":"Cytochrome P-450 CYP2E1 knockout mice are protected against high-fat diet-induced obesity and insulin resistance","volume":"302","author":"Zong","year":"2012","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"27799","DOI":"10.1038\/srep27799","article-title":"Bax Inhibitor-1 regulates hepatic lipid accumulation via ApoB secretion","volume":"6","author":"Lee","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1242\/jcs.038430","article-title":"Bax inhibitor 1 regulates ER-stress-induced ROS accumulation through the regulation of cytochrome P450 2E1","volume":"122","author":"Kim","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Kim, S.-M., Grenert, J.P., Patterson, C., and Correia, M.A. (2016). CHIP\u2212\/\u2212-Mouse Liver: Adiponectin-AMPK-FOXO-Activation Overrides CYP2E1-Elicited JNK1-Activation, Delaying Onset of NASH: Therapeutic Implications. Sci. Rep., 6.","DOI":"10.1038\/srep29423"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1172\/JCI8814","article-title":"CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis","volume":"105","author":"Leclercq","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0378-4274(99)00140-X","article-title":"Interspecies variations in fatty acid hydroxylations involving cytochromes P450 2E1 and 4A","volume":"110","author":"Adas","year":"1999","journal-title":"Toxicol. Lett."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1016\/S0022-2275(20)32422-6","article-title":"Requirement for \u03c9 and (\u03c9\u20131)-hydroxylations of fatty acids by human cytochromes P450 2E1 and 4A11","volume":"40","author":"Adas","year":"1999","journal-title":"J. Lipid Res."},{"key":"ref_123","first-page":"1121","article-title":"CYP4A11 is involved in the development of nonalcoholic fatty liver disease via ROS-induced lipid peroxidation and inflammation","volume":"45","author":"Gao","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Diesinger, T., Buko, V., Lautwein, A., Dvorsky, R., Belonovskaya, E., Lukivskaya, O., Naruta, E., Kirko, S., Andreev, V., and Buckert, D. (2020). Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0235990"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Diesinger, T., Lautwein, A., Buko, V., Belonovskaya, E., Lukivskaya, O., Naruta, E., Kirko, S., Andreev, V., Dvorsky, R., and Buckert, D. (2021). \u03c9-Imidazolyl-alkyl derivatives as new preclinical drug candidates for treating non-alcoholic steatohepatitis. Physiol. Rep., 9.","DOI":"10.14814\/phy2.14795"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1053\/j.gastro.2013.11.049","article-title":"Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease","volume":"146","author":"Lambert","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3748\/wjg.v27.i1.1","article-title":"Experimental models of metabolic and alcoholic fatty liver disease","volume":"27","author":"Buyco","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s10545-010-9061-2","article-title":"A general introduction to the biochemistry of mitochondrial fatty acid \u03b2-oxidation","volume":"33","author":"Houten","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Berardo, C., Di Pasqua, L.G., Cagna, M., Richelmi, P., Vairetti, M., and Ferrigno, A. (2020). Nonalcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: Current Issues and Future Perspectives in Preclinical and Clinical Research. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249646"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.phrs.2009.02.004","article-title":"The role of PPAR\u03b1 in lipid metabolism and obesity: Focusing on the effects of estrogen on PPAR\u03b1 actions","volume":"60","author":"Yoon","year":"2009","journal-title":"Pharmacol. Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"31581","DOI":"10.1074\/jbc.273.47.31581","article-title":"Peroxisome Proliferator-activated Receptor \u03b1 Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes","volume":"273","author":"Kroetz","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S1386-6346(00)00089-9","article-title":"Regulation of peroxisome proliferator activated receptor \u03b1-mediated pathways in alcohol fed cytochrome P450 2E1 deficient mice","volume":"19","author":"Wan","year":"2001","journal-title":"Hepatol. Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3945\/jn.110.135210","article-title":"PPAR\u03b1 Expression Protects Male Mice from High Fat\u2013Induced Nonalcoholic Fatty Liver","volume":"141","author":"Abdelmegeed","year":"2011","journal-title":"J. Nutr."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1006\/abbi.1996.9855","article-title":"Localization of Multiple Forms of Inducible Cytochromes P450 in Rat Liver Mitochondria: Immunological Characteristics and Patterns of Xenobiotic Substrate Metabolism","volume":"339","author":"Anandatheerthavarada","year":"1997","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"24680","DOI":"10.1074\/jbc.M100363200","article-title":"Mitochondrial Targeted Cytochrome P450 2E1 (P450 MT5) Contains an Intact N Terminus and Requires Mitochondrial Specific Electron Transfer Proteins for Activity","volume":"276","author":"Robin","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1039\/C7TX00020K","article-title":"Toxicological implications of mitochondrial localization of CYP2E1","volume":"6","author":"Hartman","year":"2017","journal-title":"Toxicol. Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"24609","DOI":"10.1074\/jbc.M110.121822","article-title":"Mitochondria-targeted Cytochrome P450 2E1 Induces Oxidative Damage and Augments Alcohol-mediated Oxidative Stress","volume":"285","author":"Bansal","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"6895","DOI":"10.1016\/j.febslet.2005.11.029","article-title":"Ethanol increases mitochondrial cytochrome P450 2E1 in mouse liver and rat hepatocytes","volume":"579","author":"Robin","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.3389\/fimmu.2020.01169","article-title":"Crosstalk Between Liver Macrophages and Surrounding Cells in Nonalcoholic Steatohepatitis","volume":"11","author":"Li","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Mihm, S. (2018). Danger-Associated Molecular Patterns (DAMPs): Molecular Triggers for Sterile Inflammation in the Liver. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103104"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"057","DOI":"10.1055\/s-2001-12929","article-title":"Mitochondria in Steatohepatitis","volume":"21","author":"Pessayre","year":"2001","journal-title":"Semin. Liver Dis."},{"key":"ref_142","first-page":"95","article-title":"Cytochrome P4502E1 primes macrophages to increase TNF-\u03b1 production in response to lipopolysaccharide","volume":"289","author":"Cao","year":"2005","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-017-02325-2","article-title":"Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4\u2013MD2 complex","volume":"8","author":"Kim","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1152\/physrev.1979.59.3.527","article-title":"Hydroperoxide metabolism in mammalian organs","volume":"59","author":"Chance","year":"1979","journal-title":"Physiol. Rev."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/0006-291X(80)90303-4","article-title":"Cytochrome b5 as electron donor to rabbit liver cytochrome P-450LM2 in reconstituted phospholipid vesicles","volume":"97","author":"Johansson","year":"1980","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/0163-7258(91)90020-M","article-title":"The involvement of free radicals in the mechanisms of monooxygenases","volume":"49","author":"White","year":"1991","journal-title":"Pharmacol. Ther."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.redox.2014.08.009","article-title":"The role of reactive oxygen species (ROS) and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts","volume":"3","author":"Linhart","year":"2014","journal-title":"Redox Biol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.redox.2014.09.004","article-title":"Regulation of the effects of CYP2E1-induced oxidative stress by JNK signaling","volume":"3","author":"Schattenberg","year":"2014","journal-title":"Redox Biol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.redox.2015.09.009","article-title":"Reciprocal regulation of TGF-\u03b2 and reactive oxygen species: A perverse cycle for fibrosis","volume":"6","author":"Liu","year":"2015","journal-title":"Redox Biol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1053\/jhep.2002.32969","article-title":"Mitochondrial oxidative stress and CD95 ligand: A dual mechanism for hepatocyte apoptosis in chronic alcoholism","volume":"35","author":"Lloret","year":"2002","journal-title":"Hepatology"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.metabol.2015.05.002","article-title":"Niacin inhibits fat accumulation, oxidative stress, and inflammatory cytokine IL-8 in cultured hepatocytes: Impact on non-alcoholic fatty liver disease","volume":"64","author":"Ganji","year":"2015","journal-title":"Metabolism"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1053\/jhep.2001.28888","article-title":"Alcohol-induced free radicals in mice: Direct toxicants or signaling molecules?","volume":"34","author":"Yin","year":"2001","journal-title":"Hepatology"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.jhep.2005.03.004","article-title":"NASH: A mitochondrial disease","volume":"42","author":"Pessayre","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/S0168-8278(01)00192-1","article-title":"Non-alcoholic fatty liver disease in an area of southern Italy: Main clinical, histological, and pathophysiological aspects","volume":"35","author":"Loguercio","year":"2001","journal-title":"J. Hepatol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mito.2005.10.004","article-title":"Mitochondrial dysfunction in NASH: Causes, consequences and possible means to prevent it","volume":"6","author":"Begriche","year":"2006","journal-title":"Mitochondrion"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1016\/j.ddmec.2009.02.002","article-title":"Mitochondrial dysfunction in nonalcoholic steatohepatitis (NASH): Are there drugs able to improve it?","volume":"6","author":"Begriche","year":"2009","journal-title":"Drug Discov. Today Dis. Mech."},{"key":"ref_157","first-page":"13","article-title":"The efficacy of vitamin E in reducing non-alcoholic fatty liver disease: A systematic review, meta-analysis, and meta-regression","volume":"13","author":"Menshawy","year":"2020","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1136\/postgradmedj-2018-136364","article-title":"Effect of vitamin E in non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomised controlled trials","volume":"95","author":"Amanullah","year":"2019","journal-title":"Postgrad. Med. J."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"c5702","DOI":"10.1136\/bmj.c5702","article-title":"Effects of vitamin E on stroke subtypes: Meta-analysis of randomised controlled trials","volume":"341","author":"Glynn","year":"2010","journal-title":"BMJ"},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Wang, T., and Xu, L. (2019). Circulating Vitamin E Levels and Risk of Coronary Artery Disease and Myocardial Infarction: A Mendelian Randomization Study. Nutrients, 11.","DOI":"10.3390\/nu11092153"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1001\/jama.2011.1437","article-title":"Vitamin E and the Risk of Prostate Cancer: The selenium and vitamin e cancer prevention trial (SELECT)","volume":"306","author":"Klein","year":"2011","journal-title":"JAMA"},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Wang, K., Tan, W., Liu, X., Deng, L., Huang, L., Wang, X., and Gao, X. (2021). New insight and potential therapy for NAFLD: CYP2E1 and flavonoids. Biomed. Pharmacother., 137.","DOI":"10.1016\/j.biopha.2021.111326"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"6890","DOI":"10.3748\/wjg.v22.i30.6890","article-title":"Herbal medicines and nonalcoholic fatty liver disease","volume":"22","author":"Yao","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Hurrell, T., Kastrinou-Lampou, V., Fardellas, A., Hendriks, D.F.G., Nordling, \u00c5., Johansson, I., Baze, A., Parmentier, C., Richert, L., and Ingelman-Sundberg, M. (2020). Human Liver Spheroids as a Model to Study Aetiology and Treatment of Hepatic Fibrosis. Cells, 9.","DOI":"10.3390\/cells9040964"},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Soret, P.-A., Magusto, J., Housset, C., and Gautheron, J. (2020). In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal. J. Clin. Med., 10.","DOI":"10.3390\/jcm10010036"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-32722-6","article-title":"Human hepatic 3D spheroids as a model for steatosis and insulin resistance","volume":"8","author":"Kozyra","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1096\/fj.201601375R","article-title":"Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics","volume":"31","author":"Vorrink","year":"2017","journal-title":"FASEB J."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-47737-w","article-title":"The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids","volume":"9","author":"Prill","year":"2019","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8221\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:37:59Z","timestamp":1760164679000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8221"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,30]]},"references-count":168,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22158221"],"URL":"https:\/\/doi.org\/10.3390\/ijms22158221","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,30]]}}}