{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:32:13Z","timestamp":1790253133376,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,19]],"date-time":"2025-04-19T00:00:00Z","timestamp":1745020800000},"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>Antituberculosis drug-induced hepatotoxicity (ATDH) is a common adverse drug reaction often requiring treatment interruption, complicating tuberculosis management. The slow acetylator phenotype, characterized by reduced N-acetyltransferase 2 (NAT2) enzyme activity, is associated with increased hepatotoxicity risk, while rapid acetylators are associated with a higher risk of therapeutic failure. This study investigates the association between the NAT2 acetylation phenotype and ATDH occurrence, with an emphasis on its predictive value in regard to a multiethnic population and its impact on the timing of ATDH onset. A retrospective observational study was conducted on tuberculosis patients treated at Luigi Sacco Hospital, Milan, Italy (July 2020\u2013September 2023). The NAT2 genotyping identified slow and rapid\/intermediate acetylators. Cumulative incidence analysis and Fine\u2013Gray competing risks regression models were used to assess ATDH risk and onset timing. Among 102 patients, 21.6% developed ATDH, including 16.7% with slow and 4.9% with rapid\/intermediate acetylators. ATDH onset was significantly earlier in regard to slow acetylators (median 0.5 vs. 2 months, interquartile range-IQR: 0.5\u20133 vs. 1.7\u20135.5). Slow acetylators were associated with a higher risk of developing ATDH (Sub-distribution hazard ratio, SHR = 3.05; 95% confidence interval-CI: 1.17\u20137.95; p = 0.02), even after adjusting for confounders. The NAT2 acetylation phenotype strongly influences ATDH risk and timing. Early acetylator status identification may enable dose adjustments, enhancing treatment safety. These findings highlight the role of pharmacogenetics in optimizing antituberculosis therapy by improving efficacy and minimizing toxicity.<\/jats:p>","DOI":"10.3390\/ijms26083881","type":"journal-article","created":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T20:24:16Z","timestamp":1745180656000},"page":"3881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["NAT2 Acetylation Status Predicts Hepatotoxicity During Antituberculosis Therapy: Cumulative Risk Analysis of a Multiethnic Cohort"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-1039","authenticated-orcid":false,"given":"Marco","family":"Schiuma","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0682-0138","authenticated-orcid":false,"given":"Sofia","family":"Dinegro","sequence":"additional","affiliation":[{"name":"ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Universit\u00e0 degli Studi di Milano, Via G. B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Battini","sequence":"additional","affiliation":[{"name":"ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Universit\u00e0 degli Studi di Milano, Via G. B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Torre","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5368-2883","authenticated-orcid":false,"given":"Alice","family":"Covizzi","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Civati","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Galimberti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4197-6543","authenticated-orcid":false,"given":"Ilaria","family":"Mariani","sequence":"additional","affiliation":[{"name":"ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Universit\u00e0 degli Studi di Milano, Via G. B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5162-4751","authenticated-orcid":false,"given":"Giulia","family":"Mosini","sequence":"additional","affiliation":[{"name":"ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Universit\u00e0 degli Studi di Milano, Via G. B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Carnovale","sequence":"additional","affiliation":[{"name":"ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Universit\u00e0 degli Studi di Milano, Via G. B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostino","family":"Riva","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy"},{"name":"Department of Biomedical and Clinical Sciences, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6587-4794","authenticated-orcid":false,"given":"Andrea","family":"Gori","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy"},{"name":"Department of Biomedical and Clinical Sciences, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0569-9407","authenticated-orcid":false,"given":"Spinello","family":"Antinori","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, 20157 Milan, Italy"},{"name":"Department of Biomedical and Clinical Sciences, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Clementi","sequence":"additional","affiliation":[{"name":"ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Universit\u00e0 degli Studi di Milano, Via G. B. Grassi 74, 20157 Milan, Italy"},{"name":"Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Radice","sequence":"additional","affiliation":[{"name":"ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Universit\u00e0 degli Studi di Milano, Via G. B. Grassi 74, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2837-5248","authenticated-orcid":false,"given":"Stefania","family":"Cheli","sequence":"additional","affiliation":[{"name":"ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Universit\u00e0 degli Studi di Milano, Via G. B. 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