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Ethanol in the brain is mainly metabolized into acetaldehyde by catalase and cytochrome P450 2E1 (Cyp2e1), and acetaldehyde does not freely cross the blood\u2013brain barrier. While Cyp2e1 is a well\u2010known enzyme in liver toxicology, how central nervous system (CNS)\u2010expressed Cyp2e1 contributes to ethanol toxicity is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the effects of Cyp2e1\u2010driven ethanol metabolism in the brain of male and female global Cyp2e1 knockout (KO) and wild\u2010type (WT) 129S1\/SvImJ mice. RNA\u2010seq was completed on the medial prefrontal cortex (mPFC), the dorsal and ventral hippocampus, and cerebellum to see whether there are baseline differences in gene expression between WT and KO mice. To investigate acute functional tolerance (AFT), we evaluated blood ethanol concentrations (BECs) of mice on a fixed\u2010speed rotarod after two consecutive ethanol doses. Next, we used the chronic intermittent ethanol (CIE) exposure model to study dependence\u2010induced escalation of drinking. After the study, catalase protein expression was analyzed in the mPFC, hippocampus, and cerebellum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Transcriptomic pathway analysis in ethanol\u2010na\u00efve mice revealed differences in ethanol\u2010important pathways in both male and female Cyp2e1\u2010KO mice. Glyoxylase\u20101 (\n                      <jats:italic>Glo1<\/jats:italic>\n                      ) was downregulated in KO animals. Both WT and Cyp2e1\u2010KO mice had a similar AFT. However, after both injections, Cyp2e1\u2010KO mice had to reach a lower BEC to balance on the rotarod (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), indicating increased sensitivity to ethanol intoxication. In the drinking study, Cyp2e1\u2010KO mice drank more than WT controls during baseline drinking sessions (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20098\u20139). After CIE exposure, only Cyp2e1\u2010KO mice significantly escalated their drinking (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200916\u201317). Catalase levels were not significantly higher in KO mice in the brain regions studied regardless of condition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study reveals an important role for Cyp2e1 in ethanol\u2010related behaviors and highlights a need to better understand the effects of ethanol and its metabolites in mediating ethanol drinking and sensitivity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/acer.70188","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T05:27:11Z","timestamp":1762147631000},"page":"2678-2694","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cyp2e1 deletion in mice increases sensitivity to ethanol\u2010induced motor impairment and escalation of drinking behavior in the chronic intermittent ethanol model"],"prefix":"10.1111","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2925-8457","authenticated-orcid":false,"given":"Hyland C.","family":"Gonzalez","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly R.","family":"Misare","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6662-3238","authenticated-orcid":false,"given":"Kate E.","family":"Glorioso","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe R.","family":"Delaney","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8042-6957","authenticated-orcid":false,"given":"Howard C.","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Psychiatry &amp; Behavioral Sciences Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Charleston Alcohol Research Center Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Department of Neuroscience Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5885-7371","authenticated-orcid":false,"given":"Marcelo F.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Psychiatry &amp; Behavioral Sciences Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Charleston Alcohol Research Center Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Department of Neuroscience Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Mulholland","sequence":"additional","affiliation":[{"name":"Charleston Alcohol Research Center Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Department of Neuroscience Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica H.","family":"Hartman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Medical University of South Carolina  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