河南汉族癫癎儿童UGT1A6 A541G基因多态性与丙戊酸血药浓度相关性研究

王艳; 高丽; 刘艳萍; 黄楠楠; 许淑静; 马冬菊

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中国当代儿科杂志 ›› 2010, Vol. 12 ›› Issue (06) : 429-432.

论著·临床研究

河南汉族癫癎儿童UGT1A6 A541G基因多态性与丙戊酸血药浓度相关性研究

王艳，高丽，刘艳萍，黄楠楠，许淑静，马冬菊

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Effect of UGTIA6 A541G genetic polymorphism on the metabolism of valproic acid in Han epileptic children from Henan

WANG Yan, GAO Li, LIU Yan-Ping, HUANG Nan-Nan, XU Shu-Jing, MA Dong-Ju

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摘要

目的：检测尿苷二磷酸葡糖醛酰转移酶(UGT)1A6 A541G 基因多态性在汉族癫癎患儿中的分布和突变频率，探讨UGT1A6 A541G突变各基因型与丙戊酸血药浓度的关系。方法：气相色谱法测定丙戊酸血药浓度，PCR-RFLP技术检测UGTIA6 A541G基因多态性，PCR扩增产物直接测序验证基因型检测方法的可靠性。结果：147例汉族癫癎患儿中UGTIA6 541位点的基因型AA、AG、GG分别为76例、65例和6例。服用单位剂量（mg/kg）引起的血药浓度AA基因型患儿为 3.91±1.57 μg/mL, AG基因型患儿为3.59±1.39 μg/mL, GG基因型患儿为3.73±1.28 μg/mL。AG、GG基因型患儿血药浓度较AA基因型患儿偏低，但差异无统计学意义。结论：UGT1A6 A541G基因多态性与丙戊酸的血药浓度无显著相关性，临床上个体血药浓度的差异可能是多种因素共同作用的结果。［中国当代儿科杂志，2010，12（6）：429-432］

Abstract

OBJECTIVE: To investigate the distribution and frequency of UGTIA6 A541G genetic polymorphism in Han epileptic children from Henan and to evaluate the effect of UGTIA6 A541G genetic polymorphism on serum concentrations of valproic acid. METHODS: The method of gas chromatography was used to assay serum concentrations of valproic acid. UGTIA6 A541G genetic polymorphism was screened by PCR-RFLP. Direct sequencing was used to confirm the expected sequences of each genotype. RESULTS: The genotypic frequencies of UGTIA6 A541G were as follows: AA in 76 cases, AG in 65 cases and GG in 6 cases. The mean values of serum concentrations of valproic acid in patients with A541G AA, AG and GG were 3.91±1.57, 3.59±1.39 and 3.73±1.28 μg/mL, respectively (dose-adjusted trough concentration on a mg/kg basis). There were no significant differences in serum concentrations of valproic acid among the three groups. CONCLUSIONS: UGT1A6 A541G gene polymorphism does not influence serum concentrations of valproic acid in Han epileptic children. Individual differences in serum concentrations of valproic acid may be attributed to many factors.［Chin J Contemp Pediatr, 2010, 12 (6):429-432］

导出引用

王艳, 高丽, 刘艳萍, 黄楠楠, 许淑静, 马冬菊. 河南汉族癫癎儿童UGT1A6 A541G基因多态性与丙戊酸血药浓度相关性研究[J]. 中国当代儿科杂志. 2010, 12(06): 429-432

WANG Yan, GAO Li, LIU Yan-Ping, HUANG Nan-Nan, XU Shu-Jing, MA Dong-Ju. Effect of UGTIA6 A541G genetic polymorphism on the metabolism of valproic acid in Han epileptic children from Henan[J]. Chinese Journal of Contemporary Pediatrics. 2010, 12(06): 429-432

中图分类号： R748

参考文献

［1］Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R (2004). Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care. London: Royal College of General Practitioners. http://www.nice.org.uk/.
［2］Sánchez-Alcaraz A, Quintana MB, López E, Rodríguez I. Valproic acid clearance in children with epilepsy ［J］. Clin Pharm Ther, 1998, 23(1):31-34.
［3］郑惠良,刘文弟,祁元明,杨莹,黄喜顺,景学医,等.丙戊酸钠治疗不同年龄的癫癎血药浓度研究［J］. 实用儿科临床杂志,1995,13(3):168.
［4］von Ahsen N, Richter M, Grupp C, Ringe B, Oellerich M, Armstrong VW. No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V co allele) on dose-adjusted cyclosporin Atrough ncentrations or rejection incidence in stable renal transplant recipients ［J］. Clin Chem, 2001, 47（6）:1048-1052.
［5］Nagar S, Zalatoris JJ, Blanchard RL. Human UGT1A6 pharmacogenetics: identication of a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissue and in cultured cells ［J］. Pharmacogenetics, 2004, 14（8）:487-499.
［6］Ethell BT, Anderson GD, Burchell B. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases ［J］. Biochem Pharmacol, 2003, 65(9):1441-1449.
［7］Yamagata T, Momoi MY, Murai K, Ikematsu K, Suwa K, Sakamoto K, et al. Penipenem-betamipron and decreases in serum valproic acid concentration［J］. Ther Drug Monit, 1998, 20(4):396-400.
［8］Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferase: metabolism, expression, and disease ［J］. Annu Rev Pharmacol Toxicol, 2000, 40:581-616.
［9］Urawa N, Kobayashi Y, Araki J, Sugimoto R, Iwasa M, Kaito M, et al. Linkage disequilibrium of UGT1A1*6 and UGT1A1*28 in relation to UGT1A6 and UGT1A7 polymorphisms ［J］. Oncol Rep, 2006, 16(4):801-806.
［10］Ciotti M, Marrone A, Potter C, Owens IS. Genetic polymorphism in the human UGT1A6 (planar phenol) UDP-glucuronosyl -transferase: pharmacological implications ［J］. Pharmacogenetics, 1997, 7(6):485-495.
［11］Nagar S, Zalatoris J, Blanchard R. Human UGT1A6 pharmacogenetics: identification of a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissue and in cultured cells ［J］. Pharmacogenetics, 2004, 14(8):487-499.
［12］郭栋，周红灝. UGT1A6及UGT1A1基因多态性对体内胆红素水平及对乙酰氨基酚代谢的影响［D］. 中南大学学位论文，2006.
［13］孙妍萍,谭兰，王雁，宋敬卉.尿苷二磷酸葡萄糖醛酸转移酶1A6基因多态性对丙戊酸钠代谢的影响［J］.中华医学杂志, 2007, 87(29)：2033-2035.
［14］Krishnaswamy S, Hao Q, AI-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, et al. UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most coluluon nonsynonymous UGTIA6 polymorphisms (S7A, T181A, and R184S) ［J］. Pharmacol Exp Ther, 2005, 313(3): 1340-1346.
［15］Peters WH, Morsche RH, Roelofs HM. Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications for patients with Gilbert′s syndrome ［J］. J Hepatol, 2003, 38(1): 3-8.
［16］Krishnaswamy S, Hao Q, Von Moltke LL, Greenblatt DJ, Court MH. Evaluation of 5-hydroxytryptophol and other endogenous serotonin (5-hydroxytryptamine) analogs as substrates for UDP-glucuronosyltransferase 1A6 ［J］. Drug Metab Dispos 2004, 32(8): 862-869.
［17］Chung JY, Cho JY, Yu KS, Kim JR, Lim KS, Sohn DR, et al. Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects ［J］. Clin Pharmacol Ther, 2008, 83(4):595-600.
［18］Klotz U. The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications ［J］. Clin Pharmacokinet, 2007, 46(4):271-279.
［19］Aksenova MG, Burd SG, Kachalin EIu, Avakian GN, Badalian OL, Savenkov AA, et al. An association between the FABP2 gene polymorphism and efficacy of valproates ［J］. Zh Nevrol Psikhiatr Im S S Korsakova, 2007, 107(1):42-45.