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This study investigated whether a single pretreatment with diallyl trisulfide (DATS) could suppress APAP-induced hepatotoxicity and vascular failure by directly regulating CYP2E1. DATS significantly attenuated the APAP-induced elevation of plasma AST and ALT activities and reduced hepatocyte ballooning and extensive necrosis in Zone 3. DATS also robustly suppressed pericentral fibrin deposition and hemorrhagic lesions without altering Kupffer cell accumulation. In vitro, DATS dose-dependently inhibited CYP2E1 activity, which was rescued by free cysteine. LC-MS\/MS analysis identified the CYP2E1 peptide 436-VC*VGEGLAR-444, proving specific oxidative modification at Cys437. In conclusion, a single DATS administration shuts down toxic APAP metabolism at its source via posttranslational oxidative modification of CYP2E1, comprehensively suppressing hepatocyte necrosis and intrahepatic hemorrhage. DATS is a promising fast-acting chemopreventive agent against drug-induced hepatotoxicity.<\/jats:p>","DOI":"10.1093\/bbb\/zbag129","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:51:16Z","timestamp":1787313076000},"page":"1514-1520","source":"Crossref","is-referenced-by-count":0,"title":["Diallyl trisulfide ameliorates acetaminophen-induced acute liver injury through the oxidative modification of CYP2E1 cysteine residues"],"prefix":"10.1093","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6402-0738","authenticated-orcid":false,"given":"Takashi","family":"Hosono","sequence":"first","affiliation":[{"name":"Department of Applied Life Sciences, Nihon University Graduate School of Bioresource Sciences, Fujisawa , Kanagawa 252-0880 ,","place":["Japan"]},{"name":"Department of Bioscience, Nihon University College of Bioresource Sciences, Fujisawa , Kanagawa 252-0880 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