{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T14:21:08Z","timestamp":1778422868152,"version":"3.51.4"},"reference-count":25,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,5,3]],"date-time":"2017-05-03T00:00:00Z","timestamp":1493769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81673510"],"award-info":[{"award-number":["81673510"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The aim of this study was to compare genetic polymorphisms and concentrations of hepatotoxic metabolites in patients with epilepsy and liver injury and those with normal liver function receiving valproate monotherapy to identify risk factors for<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>\u2010induced hepatotoxicity. A total of 279 Chinese patients with epilepsy were divided into an abnormal liver function (<jats:styled-content style=\"fixed-case\">ANLFT<\/jats:styled-content>) group (n = 79) and a normal liver function (<jats:styled-content style=\"fixed-case\">NLFT<\/jats:styled-content>) group (n = 200). Polymerase chain reaction\u2013restriction fragment length polymorphism<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">RFLP<\/jats:styled-content>and nested<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>were applied to identify the frequency of two<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>s in candidate genes. Serum concentrations of<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>and its major metabolites were determined by Ultra\u2010Performance Liquid Chromatography\u2013tandem mass spectrometry<jats:styled-content style=\"fixed-case\">UPLC<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content>. Significant differences were found in genotype distributions of<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2A6 and<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C9 between the two groups. The values of 4\u2010ene\u2010<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>and 2,4\u2010diene\u2010<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>in the<jats:styled-content style=\"fixed-case\">ANLFT<\/jats:styled-content>group were significantly higher than in the<jats:styled-content style=\"fixed-case\">NLFT<\/jats:styled-content>group. Only<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2A6 polymorphisms had associations with the concentrations of 4\u2010ene\u2010<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>and 2,4\u2010diene\u2010<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>.<jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2A6*1\/*4<\/jats:italic>and<jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2A6*4\/*4<\/jats:italic>variant carriers had higher<jats:styled-content style=\"fixed-case\">CDR<\/jats:styled-content><jats:sub>4\u2010ene\u2010<\/jats:sub><jats:styled-content style=\"fixed-case\"><jats:sub>VPA<\/jats:sub><\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">CDR<\/jats:styled-content><jats:sub>2,4\u2010diene\u2010<\/jats:sub><jats:styled-content style=\"fixed-case\"><jats:sub>VPA<\/jats:sub><\/jats:styled-content>values than<jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2A6*1\/*1<\/jats:italic>carriers. The logistic regression analysis showed that<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C9 and<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2A6 were significant risk factors for hepatotoxicity by increasing the risk by 7.50 and 5.13 times, respectively. These findings provide preliminary evidence that<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2A6 and<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C9 are associated with hepatotoxicity. However, only the<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2A6 polymorphism was found to be associated with concentrations of 4\u2010ene\u2010<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>and 2,4\u2010diene\u2010<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>. Potential important risk factors include mutated genotypes of<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2C9 and<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2A6 and higher concentrations of<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>, 4\u2010ene\u2010<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>and 2,4\u2010diene\u2010<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/bcpt.12776","type":"journal-article","created":{"date-parts":[[2017,3,8]],"date-time":"2017-03-08T18:26:44Z","timestamp":1488997604000},"page":"138-143","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Associations of<scp>CYP<\/scp>2C9 and<scp>CYP<\/scp>2A6 Polymorphisms with the Concentrations of Valproate and its Hepatotoxin Metabolites and Valproate\u2010Induced Hepatotoxicity"],"prefix":"10.1111","volume":"121","author":[{"given":"Mingming","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of pharmacy Shengjing Hospital of China Medical University Shenyang Liaoning Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ti","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of pharmacy Shengjing Hospital of China Medical University Shenyang Liaoning Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guofei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of pharmacy Shengjing Hospital of China Medical University Shenyang Liaoning Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of pharmacy Shengjing Hospital of China Medical University Shenyang Liaoning Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaxin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of pharmacy Shengjing Hospital of China Medical University Shenyang Liaoning Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Limei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of pharmacy Shengjing Hospital of China Medical University Shenyang Liaoning Province China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,5,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.37.3.379"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.09.111"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.45.120403.100058"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408440590935620"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840040610"},{"key":"e_1_2_8_7_1","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/S0090-9556(25)08858-0","article-title":"Biotransformation and pharmacokinetics in the rhesus monkey of 2\u2010n\u2010propyl\u20104\u2010pentenoic acid, a toxic metabolite of valproic acid","volume":"14","author":"Rettenmeier AW","year":"1986","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0090-9556(25)07823-7","article-title":"Studies on the biotransformation in the perfused rat liver of 2\u2010n\u2010propyl\u20104\u2010pentenoic acid, a metabolite of the antiepileptic drug valproic acid. 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