Abstract：
UNASSIGNED: Although valproic acid is generally well tolerated, hepatotoxicity is a common side effect in patients receiving long-term treatment. However, the mechanisms underlying valproic acid-associated hepatotoxicity remain elusive.
UNASSIGNED: To investigate the mechanisms and explore the potential risk factors for valproic acid-associated hepatotoxicity, 165 age-matched pediatric patients were recruited for laboratory tests and glutamate-glutamine cycle analysis.
UNASSIGNED: The concentration of glutamate in patients with hepatotoxicity was significantly greater than that in control patients, while the concentration of glutamine in patients with hepatotoxicity was significantly lower than that in control patients (P <0.05). In addition, the frequencies of the heterozygous with one mutant allele and homozygous with two mutant alleles genotypes in glutamate-ammonia ligase rs10911021 were significantly higher in the hepatotoxicity group than those in the control group (47.1 percent versus 32.5 percent, P = 0.010; 17.6 percent versus 5.2 percent, P = 0.001, respectively). Moreover, heterozygous carriers with one mutant allele and homozygous carriers with two mutant alleles genotypes of glutamate-ammonia ligase rs10911021 exhibited significant differences in the concentrations of glutamine and glutamate concentrations (P ˂ 0.001 and P = 0.001, respectively) and liver function indicators (activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase, P <0.001, respectively). Furthermore, logistic regression analysis indicated that glutamate-ammonia ligase rs10911021 (P = 0.002, odds ratio: 3.027, 95 percent confidence interval, 1.521 - 6.023) and glutamate (P = 0.001, odds ratio: 2.235, 95 percent confidence interval, 1.369 - 3.146) were associated with a greater risk for hepatotoxicity, while glutamine concentrations were negatively associated with hepatotoxicity (P = 0.001, odds ratio: 0.711, 95 percent confidence interval, 0.629 - 0.804).
UNASSIGNED: Understanding pharmacogenomic risks for valproic acid induced hepatotoxicity might help direct patient specific care. Limitations of our study include the exclusive use of children from one location and concomitant medication use in many patients.
UNASSIGNED: Perturbation of the glutamate-glutamine cycle is associated with valproic acid-associated hepatotoxicity. Moreover, glutamate-ammonia ligase rs10911021, glutamate and glutamine concentrations are potential risk factors for valproic acid-associated hepatotoxicity.
UNASSIGNED: To investigate the mechanisms and explore the potential risk factors for valproic acid-associated hepatotoxicity, 165 age-matched pediatric patients were recruited for laboratory tests and glutamate-glutamine cycle analysis.
UNASSIGNED: The concentration of glutamate in patients with hepatotoxicity was significantly greater than that in control patients, while the concentration of glutamine in patients with hepatotoxicity was significantly lower than that in control patients (P <0.05). In addition, the frequencies of the heterozygous with one mutant allele and homozygous with two mutant alleles genotypes in glutamate-ammonia ligase rs10911021 were significantly higher in the hepatotoxicity group than those in the control group (47.1 percent versus 32.5 percent, P = 0.010; 17.6 percent versus 5.2 percent, P = 0.001, respectively). Moreover, heterozygous carriers with one mutant allele and homozygous carriers with two mutant alleles genotypes of glutamate-ammonia ligase rs10911021 exhibited significant differences in the concentrations of glutamine and glutamate concentrations (P ˂ 0.001 and P = 0.001, respectively) and liver function indicators (activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase, P <0.001, respectively). Furthermore, logistic regression analysis indicated that glutamate-ammonia ligase rs10911021 (P = 0.002, odds ratio: 3.027, 95 percent confidence interval, 1.521 - 6.023) and glutamate (P = 0.001, odds ratio: 2.235, 95 percent confidence interval, 1.369 - 3.146) were associated with a greater risk for hepatotoxicity, while glutamine concentrations were negatively associated with hepatotoxicity (P = 0.001, odds ratio: 0.711, 95 percent confidence interval, 0.629 - 0.804).
UNASSIGNED: Understanding pharmacogenomic risks for valproic acid induced hepatotoxicity might help direct patient specific care. Limitations of our study include the exclusive use of children from one location and concomitant medication use in many patients.
UNASSIGNED: Perturbation of the glutamate-glutamine cycle is associated with valproic acid-associated hepatotoxicity. Moreover, glutamate-ammonia ligase rs10911021, glutamate and glutamine concentrations are potential risk factors for valproic acid-associated hepatotoxicity.
摘要：
■尽管丙戊酸通常具有良好的耐受性，肝毒性是接受长期治疗的患者的常见副作用。然而,丙戊酸相关肝毒性的潜在机制仍然难以捉摸.
■为了研究丙戊酸相关肝毒性的机制和潜在危险因素，招募了165例年龄匹配的儿科患者进行实验室测试和谷氨酸-谷氨酰胺循环分析。
■肝毒性患者的谷氨酸浓度明显高于对照组患者，肝毒性患者谷氨酰胺浓度显著低于对照组(P<0.05)。此外,谷氨酸氨连接酶rs10911021中具有一个突变等位基因的杂合子和具有两个突变等位基因的纯合子基因型的频率在肝毒性组中明显高于对照组（47.1％对32.5％，P=0.010；17.6%对5.2%，分别为P=0.001)。此外，具有一个突变等位基因的杂合携带者和具有两个突变等位基因基因型的谷氨酸-氨连接酶rs10911021的纯合携带者在谷氨酰胺浓度和谷氨酸浓度（分别为P=0.001和P=0.001）和肝功能指标（谷草转氨酶活性，丙氨酸氨基转移酶，和γ-谷氨酰转移酶，P分别为0.001)。此外，logistic回归分析显示谷氨酸-氨连接酶rs10911021(P=0.002,比值比:3.027,95%置信区间,1.521-6.023)和谷氨酸(P=0.001，比值比：2.235，95%置信区间，1.369-3.146)与肝毒性的更大风险相关，而谷氨酰胺浓度与肝毒性呈负相关(P=0.001,比值比:0.711,95%置信区间,0.629-0.804）。
■了解丙戊酸诱导肝毒性的药物基因组风险可能有助于指导患者的具体治疗。我们研究的局限性包括仅从一个位置使用儿童，并在许多患者中同时使用药物。
■谷氨酸-谷氨酰胺循环的扰动与丙戊酸相关的肝毒性相关。此外，谷氨酸-氨连接酶rs10911021，谷氨酸和谷氨酰胺浓度是丙戊酸相关肝毒性的潜在危险因素。
■为了研究丙戊酸相关肝毒性的机制和潜在危险因素，招募了165例年龄匹配的儿科患者进行实验室测试和谷氨酸-谷氨酰胺循环分析。
■肝毒性患者的谷氨酸浓度明显高于对照组患者，肝毒性患者谷氨酰胺浓度显著低于对照组(P<0.05)。此外,谷氨酸氨连接酶rs10911021中具有一个突变等位基因的杂合子和具有两个突变等位基因的纯合子基因型的频率在肝毒性组中明显高于对照组（47.1％对32.5％，P=0.010；17.6%对5.2%，分别为P=0.001)。此外，具有一个突变等位基因的杂合携带者和具有两个突变等位基因基因型的谷氨酸-氨连接酶rs10911021的纯合携带者在谷氨酰胺浓度和谷氨酸浓度（分别为P=0.001和P=0.001）和肝功能指标（谷草转氨酶活性，丙氨酸氨基转移酶，和γ-谷氨酰转移酶，P分别为0.001)。此外，logistic回归分析显示谷氨酸-氨连接酶rs10911021(P=0.002,比值比:3.027,95%置信区间,1.521-6.023)和谷氨酸(P=0.001，比值比：2.235，95%置信区间，1.369-3.146)与肝毒性的更大风险相关，而谷氨酰胺浓度与肝毒性呈负相关(P=0.001,比值比:0.711,95%置信区间,0.629-0.804）。
■了解丙戊酸诱导肝毒性的药物基因组风险可能有助于指导患者的具体治疗。我们研究的局限性包括仅从一个位置使用儿童，并在许多患者中同时使用药物。
■谷氨酸-谷氨酰胺循环的扰动与丙戊酸相关的肝毒性相关。此外，谷氨酸-氨连接酶rs10911021，谷氨酸和谷氨酰胺浓度是丙戊酸相关肝毒性的潜在危险因素。
