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 CDR and CDR values 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.

Impact of gender, albumin, and CYP2C19 polymorphisms on valproic acid in Chinese patients: a population pharmacokinetic model

“…The genetic factors affecting VPA pharmacokinetics/metabolism in vivo include ABCC2, CYP2A6, CYP2C9, CYP2C19, LEPR, the UGT series genes, and the SCN series genes. 4 , 7 , 8 , 17 , 22 , 23 The following physiological factors were included: weight, age, gender, height, and body surface area. 5 Pathological factors included the epilepsy type and liver and kidney function, whilst other factors that were included comprised medication and total daily dose.…”

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure

“…11,12 Valproic acid (VPA) is widely prescribed for epilepsy and used as an anticonvulsant, which is eliminated by biotransformation through multiple pathways, including glucuronidation, cytochrome P-450 metabolism, and mitochondrial b-oxidation. 13 Besides inducing metabolic syndrome in overweight epileptic patients, 14,15 long-term VPA therapy can cause hepatotoxicity that may progress to idiosyncratic ALF. 13,16 VPA-mediated hepatotoxicity is characterized by necrosis, depletion of endogenous antioxidants, and disruption of mitochondrial b-oxidation of fatty acids, which can contribute to hepatic steatosis.…”

“…13 Besides inducing metabolic syndrome in overweight epileptic patients, 14,15 long-term VPA therapy can cause hepatotoxicity that may progress to idiosyncratic ALF. 13,16 VPA-mediated hepatotoxicity is characterized by necrosis, depletion of endogenous antioxidants, and disruption of mitochondrial b-oxidation of fatty acids, which can contribute to hepatic steatosis. [16][17][18][19][20] Furthermore, VPA has been shown to inhibit HDAC and GSK3 signaling events, 21,22 and although reported to induce endoplasmic reticulum stress (ER stress), 23,24 there are studies showing that VPA protects cells against ER stressmediated apoptosis and atherosclerosis.…”

Therapeutic Drug Monitoring Characteristics in a Tertiary University Hospital in 2019

“…This might be interpreted as undertreatment. VALP metabolism was also altered with CYP2C9 and CYP2A6 polymorphisms [7]. Pharmacogenetics testing might contribute to a better understanding of the pharmacokinetic variability observed between individuals.…”