Role of <i>CYP2C9</i> polymorphism in valproate-related lipidmetabolic in epilepsy children_Journal of Epilepsy

Authors：

LIN Qing-shuang ¹ , ZHENG Lili ¹ , HUI Xiaoyu ² ,  WENG Aibin ¹

1. Department of Clinical Pharmacology, The Affiliated Hospital (Group) of Putian University, Putian 351100, China;
2. Pharmaceutical and Medical Technology College of Putian University, Putian 351100, China;

Corresponding author：

WENG Aibin, Email: fjptyyyjk@163.com

Keywords：

Epilepsy; CYP2C9; Valproic acid; Lipid; Subclinical atherosclerosis

DOI：

10.7507/2096-0247.202112004

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Objective To investigated the influence of the CYP2C9 polymorphism on lipid profile and blood concentration in epileptic children with VPA. Methods This study collected the information of healthy children and epilepsy children who were treated with VPA in the First Affiliated Hospital of Putian University during June, 2018 to March, 2021. The serum lipids of 184 cases were collected and compared between epilepsy group before and after treatment with VPA with the control group. The polymorphism of CYP2C9 gene in children with epilepsy was detected, and lipid and VPA concentration were compared after classification. Results There was no significant difference in lipid between the control group and the epilepsy group before treatment (P>0.05); The TC, HDL, LDL, TC/HDL, LDL/HDL were statistically different in VPA treatment group from the control group (P<0.05), and there were statistical differences in TG, LDL, TC/HDL, LDL/HDL between the trial group before the initiation and VPA treatment (P<0.05); There is no correlation between VPA blood concentration and lipid (P>0.05). VPA concentration, TC, HDL, LDL, TC/HDL and LDL/HDL in CYP2C9 wild-type were statistically different from heterozygous mutant. Conculsions CYP2C9 polymorphism and long-term use of VPA caused the changes in serum lipid levels in epilepsy children.

Citation： LIN Qing-shuang, ZHENG Lili, HUI Xiaoyu, WENG Aibin. Role of CYP2C9 polymorphism in valproate-related lipidmetabolic in epilepsy children. Journal of Epilepsy, 2022, 8(4): 312-315. doi: 10.7507/2096-0247.202112004 Copy

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2.	Lopinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Curr Treat Options Neurol, 2010, 12(4): 300-308.
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8.	赵阳阳, 许智慧, 刘妍, 等. 细胞色素P450基因多态性与药物代谢研究进展. 临床药物治疗杂志, 2017, 15(4): 1-6.
9.	Xiong Y, Wang M, Fang K, et al. A systematic genetic polymorphism analysis of the CYP2C9 gene in four different geographical Han popu lations in mainland China. Genomics, 2011, 97(5): 277-281.
10.	何知广, 黄汉辉, 罗运好, 等. 丙戊酸钠对癫痫患儿脂质代谢的影响. 中国药师, 2010, 13(4): 546-547.
11.	Budi, T, Toth, K, Nagy A, et al. Clinical significance of CYP2C9-status guided valproic acid therapy in children. Epilepsia, 2015, 56(6): 849-855.
12.	Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and imp act of genetic variation. Pharmacol Ther, 2013, 138(1): 103-141.
13.	Anderson GD. Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs . Neurology, 2004, 63(Suppl 4): 3-8.
14.	Gaikwad T, Ghosh K, Shetty S. VKORC1 and CYP2C9 genotype distribution in Asian countries. Thromb Res, 2014, 134(3): 537-544.
15.	Yoon HY, Ahn MH, Yee J, et al. Influence of CYP2C9 and CYP2A6 on plasma concentrations of valproic acid: a meta-analysis. Eur J Clin Pharmacol, 2020, 76(8): 1053-1058.
16.	Phabphal K, Geater A, Limapichart K, et al. Role of CYP2C9 polymorphism in phenytoin-related metabolic abnormalities and subclinical atherosclerosis in young adult epileptic patients. Seizure, 2013, 22(2): 103-108.
17.	Donato MT, Lahoz A, Jimnez N, et al. Potential impact of steatosis on cytochrome P450 enzymes of human hepatocytes isolated from fatty liv er grafts. Drug Metab Dispos, 2006, 34(9): 1556-1562.
18.	Monostory K, Nagy A, Toth K, et al. Relevance of CYP2C9 Function in Valproate Therapy. Curr Neuropharmacol, 2019, 17(1): 99-106.

1. Karakaya Z, Cavkaytar E, Tosun M, et al. Subclinical cardiovascular dysfunction in children and adolescents with asthma. J Asthma, 2020, 115: 1-15.
2. Lopinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Curr Treat Options Neurol, 2010, 12(4): 300-308.
3. 赵晶, 冯伟, 罗新民, 等. 丙戊酸钠对成人癫痫患者脂质代谢的影响. 中国新药与临床杂志, 2010, 29(3): 203-206.
4. Fisslthaler B, Popp R, Kiss L, et al. Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature, 1999, 401(6752): 493-497.
5. Fleming I, Michaelis UR, Bredenkotter D, et al. Endothelium-derived hyperpolarizing factor synthase (Cytochrome P450 2C9) is a functionally significant source of reactive oxygen species in coronary arteries. Circ Res, 2001, 88(1): 44-51.
6. 尹胜菊, 许新升, 刘新风, 等. 细胞色素P450 2C9基因多态性与癫痫易感性及其与丙戊酸血清浓度相关性. 中国临床药理学杂志, 2017, 33(19): 1906-1908.
7. 沈建玲, 李惠英, 任丹阳, 等. 丙戊酸的相关代谢酶基因多态性研究进展. 海峡药学, 2019, 31(4): 100-103.
8. 赵阳阳, 许智慧, 刘妍, 等. 细胞色素P450基因多态性与药物代谢研究进展. 临床药物治疗杂志, 2017, 15(4): 1-6.
9. Xiong Y, Wang M, Fang K, et al. A systematic genetic polymorphism analysis of the CYP2C9 gene in four different geographical Han popu lations in mainland China. Genomics, 2011, 97(5): 277-281.
10. 何知广, 黄汉辉, 罗运好, 等. 丙戊酸钠对癫痫患儿脂质代谢的影响. 中国药师, 2010, 13(4): 546-547.
11. Budi, T, Toth, K, Nagy A, et al. Clinical significance of CYP2C9-status guided valproic acid therapy in children. Epilepsia, 2015, 56(6): 849-855.
12. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and imp act of genetic variation. Pharmacol Ther, 2013, 138(1): 103-141.
13. Anderson GD. Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs . Neurology, 2004, 63(Suppl 4): 3-8.
14. Gaikwad T, Ghosh K, Shetty S. VKORC1 and CYP2C9 genotype distribution in Asian countries. Thromb Res, 2014, 134(3): 537-544.
15. Yoon HY, Ahn MH, Yee J, et al. Influence of CYP2C9 and CYP2A6 on plasma concentrations of valproic acid: a meta-analysis. Eur J Clin Pharmacol, 2020, 76(8): 1053-1058.
16. Phabphal K, Geater A, Limapichart K, et al. Role of CYP2C9 polymorphism in phenytoin-related metabolic abnormalities and subclinical atherosclerosis in young adult epileptic patients. Seizure, 2013, 22(2): 103-108.
17. Donato MT, Lahoz A, Jimnez N, et al. Potential impact of steatosis on cytochrome P450 enzymes of human hepatocytes isolated from fatty liv er grafts. Drug Metab Dispos, 2006, 34(9): 1556-1562.
18. Monostory K, Nagy A, Toth K, et al. Relevance of CYP2C9 Function in Valproate Therapy. Curr Neuropharmacol, 2019, 17(1): 99-106.

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