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]
WANG Yan,GAO Li,LIU Yan-Ping et al. Effect of UGTIA6 A541G genetic polymorphism on the metabolism of valproic acid in Han epileptic children from Henan[J]. CJCP, 2010, 12(06): 429-432.
[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.
[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.
[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.
[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.