{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T06:18:46Z","timestamp":1790489926638,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":4383,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2003,9]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>After several weeks of treatment, levels of alanine aminotransferase (ALT) increase in 50% of patients treated with tacrine for Alzheimer's disease. We looked for progressive effects on DNA to explain delayed toxicity. We first studied the <jats:italic toggle=\"yes\">in vitro<\/jats:italic> effects of tacrine on DNA replication and topoisomerase\u2013mediated DNA relaxation. We then treated mice with doses of tacrine reproducing the human daily dose on a body area basis and studied the effects of tacrine administration for up to 28 days on hepatic DNA, mitochondrial function, and cell death. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, tacrine impaired DNA polymerase \u03b3\u2013mediated DNA replication and also poisoned topoisomerases I and II to increase the relaxation of a supercoiled plasmid. <jats:italic toggle=\"yes\">In vivo<\/jats:italic>, administration of tacrine markedly decreased incorporation of [<jats:sup>3<\/jats:sup>H]thymidine into mitochondrial DNA (mtDNA), progressively and severely depleted mtDNA, and partly unwound supercoiled mtDNA into circular mtDNA. Incorporation of [<jats:sup>3<\/jats:sup>H]thymidine into nuclear DNA (nDNA) was barely decreased, and nDNA levels were unchanged. After 12 to 28 days of treatment, administration of tacrine increased p53, Bax, mitochondrial permeability transition, cytosolic cytochrome <jats:italic toggle=\"yes\">c<\/jats:italic>, and caspase\u20133 activity and triggered hepatocyte apoptosis and\/or necrosis. In conclusion, the intercalating drug tacrine poisons topoisomerases and impairs DNA synthesis. Tacrine has been shown to accumulate within mitochondria, and it particularly targets mtDNA. After several weeks of treatment, the combination of severe mtDNA depletion and a genotoxic stress enhancing p53, Bax, and permeability transition trigger hepatocyte necrosis and\/or apoptosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1053\/jhep.2003.50353","type":"journal-article","created":{"date-parts":[[2003,9,23]],"date-time":"2003-09-23T22:01:25Z","timestamp":1064354485000},"page":"715-725","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":68,"title":["Tacrine Inhibits Topoisomerases and Dna Synthesis to Cause Mitochondrial Dna Depletion and Apoptosis in Mouse 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