title: Associations of CYP2C9 and CYP2A6 Polymorphisms with the Concentrations of Valproate and its Hepatotoxin Metabolites and Valproate-Induced Hepatotoxicity.
abstract: 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 VPA-induced hepatotoxicity. A total of 279 Chinese patients with epilepsy were divided into an abnormal liver function (ANLFT) group (n = 79) and a normal liver function (NLFT) group (n = 200). Polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP and nested PCR were applied to identify the frequency of two SNPs in candidate genes. Serum concentrations of VPA and its major metabolites were determined by Ultra-Performance Liquid Chromatography-tandem mass spectrometry UPLC-MS/MS. Significant differences were found in genotype distributions of CYP2A6 and CYP2C9 between the two groups. The values of 4-ene-VPA and 2,4-diene-VPA in the ANLFT group were significantly higher than in the NLFT group. Only CYP2A6 polymorphisms had associations with the concentrations of 4-ene-VPA and 2,4-diene-VPA. CYP2A6*1/*4 and CYP2A6*4/*4 variant carriers had higher CDR4-ene-VPAand CDR2,4-diene-VPAvalues than CYP2A6*1/*1 carriers. The logistic regression analysis showed that CYP2C9 and CYP2A6 were significant risk factors for hepatotoxicity by increasing the risk by 7.50 and 5.13 times, respectively. These findings provide preliminary evidence that CYP2A6 and CYP2C9 are associated with hepatotoxicity. However, only the CYP2A6 polymorphism was found to be associated with concentrations of 4-ene-VPA and 2,4-diene-VPA. Potential important risk factors include mutated genotypes of CYP2C9 and CYP2A6 and higher concentrations of VPA, 4-ene-VPA and 2,4-diene-VPA.
authors.affiliation: Department of pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
authors.forename: Guofei
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002681:China; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy; D005229:Fatty Acids, Monounsaturated / Q000097:blood; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006785:Hospitals, University; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D014635:Valproic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: C556631:2,4-diene-valproic acid; D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; C045022:2-propyl-4-pentenoic acid; D014635:Valproic Acid; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6