Association of CYP2C9, CYP2A6, ACSM2A, and CPT1A gene polymorphisms with adverse effects of valproic acid in Chinese patients with epilepsy.
To explore the influence of CYP2C9, CYP2A6, ACSM2A, CPT1A gene polymorphisms on valproic acid (VPA) and its role in metabolism-related liver dysfunction in order to guide the clinical safety and rational use of VPA.



One hundred two patients taking sodium valproate oral solution were genotyped. To assess the genotypes of relevant genes, the CYP2C9 gene was directly sequenced; for polymorphism classification, multiple Long-PCR electrophoresis was conducted for CYP2A6; and imLDR method was used for ACSM2A and CPT1A. GC-MS-SIM was used to determine the levels of VPA and 2-propyl-4-pentenoic acid (4-ene-VPA) in human plasma simultaneously.



CYP2C9 mutations had a significant impact on 4-ene-VPA concentration, in patients with wild-type CYP2C9 (CYP2C9*1), which has a greater capacity for VPA metabolism than the mutant type (CYP2C9*3), liver dysfunction was substantially higher. Patients with an ACSM2A polymorphism had higher levels of ALT and AST compared with wild-type (p<0.05), but the mutations had no effect on the VPA-related liver dysfunction (p>0.05). Among different CYP2A6 and CPT1A genotype groups, there was no significant correlation in the levels of VPA, 4-ene-VPA, ALT, AST or TB (p>0.05). The content of 4-ene-VPA had no direct correlation with the incidence of liver dysfunction.



Early detection of CYP2C9 gene polymorphisms may help to predict or prevent liver dysfunction caused by VPA. While the concentration of 4-ene-VPA was not suitable as an early warning index, the results provide clear theoretical guidance for the rational and safe clinical use of VPA.
Pharmaceutical Department, Xiangya Hospital, Central South University, Changsha, 410008, China; Pharmaceutical Department, Hunan Cancer Hospital, The Affiliated Cancer Hospital Of Xiangya School Of Medicine, Central South University, Changsha, 410013, China.
Can
C
Wang
Pharmaceutical Department, Xiangya Hospital, Central South University, Changsha, 410008, China.
Ping
P
Wang
Pharmaceutical Department, Hunan Cancer Hospital, The Affiliated Cancer Hospital Of Xiangya School Of Medicine, Central South University, Changsha, 410013, China.
Li-Ping
LP
Yang
Clinical Trial Agency of Drugs, Xiangya Hospital, Central South University, Changsha, 410008, China.
Jing
J
Pan
Pharmaceutical Department, Xiangya Hospital, Central South University, Changsha, 410008, China.
Xue
X
Yang
Pharmaceutical Department, Xiangya Hospital, Central South University, Changsha, 410008, China; Institute Of Hospital Pharmacy, Central South University, Changsha, 410008, China. Electronic address: 1063701119@qq.com.
Hong-Ying
HY
Ma
D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D044466:Asian People; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D003066:Coenzyme A Ligases / Q000235:genetics; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D014635:Valproic Acid / Q000009:adverse effects* / Q000627:therapeutic use
D000927:Anticonvulsants; D014635:Valproic Acid; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; D003066:Coenzyme A Ligases; C540758:ACSM2A protein, human
2-propyl-4-pentenoic acid; Epilepsy; Gene polymorphism; Liver dysfunction; Valproic acid