{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:08:05Z","timestamp":1792098485895,"version":"4.4.0"},"reference-count":18,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1765,"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":[[2010,11]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>Sodium valproate (VPA) is widely used throughout the world to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy. VPA toxicity is an uncommon but potentially fatal cause of idiosyncratic liver injury. Rare mutations in<\/jats:bold>\n                      <jats:bold>POLG<\/jats:bold>\n                      <jats:bold>, which codes for the mitochondrial DNA polymerase \u03b3 (pol\u03b3), cause Alpers-Huttenlocher syndrome (AHS). AHS is a neurometabolic disorder associated with an increased risk of developing fatal VPA hepatotoxicity. We therefore set out to determine whether common genetic variants in<\/jats:bold>\n                      <jats:bold>POLG<\/jats:bold>\n                      <jats:bold>explain why some otherwise healthy individuals develop VPA hepatotoxicity. We carried out a prospective study of subjects enrolled in the Drug Induced Liver Injury Network (DILIN) from 2004 to 2008 through five US centers.<\/jats:bold>\n                      <jats:bold>POLG<\/jats:bold>\n                      <jats:bold>was sequenced and the functional consequences of VPA and novel<\/jats:bold>\n                      <jats:bold>POLG<\/jats:bold>\n                      <jats:bold>variants were evaluated in primary human cell lines and the yeast model system<\/jats:bold>\n                      <jats:bold>Saccharomyces cerevisiae<\/jats:bold>\n                      <jats:bold>. Heterozygous genetic variation in<\/jats:bold>\n                      <jats:bold>POLG<\/jats:bold>\n                      <jats:bold>was strongly associated with VPA-induced liver toxicity (odds ratio = 23.6, 95% confidence interval [CI] = 8.4-65.8,<\/jats:bold>\n                      <jats:bold>P<\/jats:bold>\n                      <jats:bold>= 5.1 \u00d7 10\u22127). This was principally due to the p.Q1236H substitution which compromised pol\u03b3 function in yeast. Therapeutic doses of VPA inhibited human cellular proliferation and high doses caused nonapoptotic cell death, which was not mediated through mitochondrial DNA depletion, mutation, or a defect of fatty acid metabolism.<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      <jats:bold>These findings implicate impaired liver regeneration in VPA toxicity and show that prospective genetic testing of<\/jats:bold>\n                      <jats:bold>POLG<\/jats:bold>\n                      <jats:bold>will identify individuals at high risk of this potentially fatal consequence of treatment. (Hepatology 2010;52:1791-1796)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.23891","type":"journal-article","created":{"date-parts":[[2010,8,5]],"date-time":"2010-08-05T19:30:19Z","timestamp":1281036619000},"page":"1791-1796","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":226,"title":["Polymerase \u03b3 Gene POLG Determines the Risk of Sodium Valproate-Induced Liver Toxicity"],"prefix":"10.1097","volume":"52","author":[{"given":"Joanna D.","family":"Stewart","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Baruffini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iliana","family":"Ferrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Bulst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul B.","family":"Watkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Fontana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Day","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick F.","family":"Chinnery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R2-29-20250312","doi-asserted-by":"crossref","first-page":"465469","DOI":"10.1212\/WNL.46.2.465","article-title":"3rd, Dreifuss FE. Valproic acid hepatic fatalities. III. U.S. experience since 1986.","volume":"46","author":"Bryant","year":"1996","journal-title":"Neurology"},{"key":"R3-29-20250312","doi-asserted-by":"crossref","first-page":"5568","DOI":"10.2165\/00002018-200932010-00005","article-title":"DrugInduced Liver Injury Network (DILIN) prospective study: rationale, design and conduct.","volume":"32","author":"Fontana","year":"2009","journal-title":"Drug Saf"},{"key":"R4-29-20250312","doi-asserted-by":"crossref","first-page":"322328","DOI":"10.1046\/j.1528-1157.2003.07202.x","article-title":"Effects of age and polytherapy, risk factors of valproic acid (VPA) hepatotoxicity, on the excretion of thiol conjugates of (E)2,4diene VPA in people with epilepsy taking VPA.","volume":"44","author":"Gopaul","year":"2003","journal-title":"Epilepsia"},{"key":"R5-29-20250312","doi-asserted-by":"crossref","first-page":"706712","DOI":"10.1002\/ana.20079","article-title":"POLG mutations associated with Alpers syndrome and mitochondrial DNA 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workshop: Polymerase gamma and disorders of mitochondrial DNA synthesis, 2123 September 2007, Naarden, The Netherlands.","volume":"18","author":"Chinnery","year":"2007","journal-title":"Neuromuscul Disord"},{"key":"R10-29-20250312","doi-asserted-by":"crossref","first-page":"453455","DOI":"10.1212\/01.wnl.0000171861.30277.88","article-title":"Mitochondrial DNA copy number threshold in mtDNA depletion myopathy.","volume":"65","author":"Durham","year":"2005","journal-title":"Neurology"},{"key":"R11-29-20250312","doi-asserted-by":"crossref","first-page":"20272031","DOI":"10.1111\/j.1528-1167.2006.00846.x","article-title":"Valproic acidinduced hepatopathy: nine new fatalities in Germany from 1994 to 2003.","volume":"47","author":"Koenig","year":"2006","journal-title":"Epilepsia"},{"key":"R12-29-20250312","doi-asserted-by":"crossref","first-page":"15901599","DOI":"10.1093\/hmg\/ddp074","article-title":"In vitro supplementation with dAMPdGMP leads to partial restoration of mtDNA levels in 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