Huang Zhen, Wang Juxiang, Qian Jiangchao, Li Yuan, Xu Zhisheng, Chen Min, Tong Hongfei
Department of Hematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China.
Department of Hepatobiliary Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China.
Mol Med Rep. 2017 Jun;15(6):3493-3498. doi: 10.3892/mmr.2017.6470. Epub 2017 Apr 12.
The present study aimed to investigate the association between the genetic polymorphism of cytochrome P450 family 3 subfamily A member 5 (CYP3A5) and the activity of CYP3A and plasma concentrations of daunorubicin (DNR) in patients with acute leukemia. A total of 36 children with newly diagnosed acute lymphoblastic leukemia were enrolled in the study. Polymerase chain reaction (PCR)‑restriction fragment length polymorphism and PCR product sequencing were used to detect the genotype of CYP3A53. PCR was then used to express the mRNA expression of CYP3A5. A midazolam probe method was used to detect CYP3A enzyme activity, and DNR concentrations were measured using high performance liquid chromatography. Children with different genotypes had different mRNA expression levels of CYP3A5, and CYP3A enzyme activity in children with the CYP3A51 allele was higher, compared with that in children with the CYP3A53 allele. In addition, the area under the curve (AUC)0‑24 h and AUC0‑∞ of DNR were significantly different in children with different genotypes, however, no statistically significant differences were found in half‑life or maximum concentration. The AUC of DNR was increased in children with acute lymphatic leukemia who suffered from cardiotoxicity, compared with those in the normal group. The CYP3A53 gene polymorphism was closely associated with the mRNA expression of CYP3A5, CYP3A enzyme activity and DNR plasma drug concentration, and exhibited different drug adverse reactions.
本研究旨在探讨细胞色素P450家族3亚家族A成员5（CYP3A5）基因多态性与急性白血病患者CYP3A活性及柔红霉素（DNR）血药浓度之间的关系。本研究共纳入36例新诊断的急性淋巴细胞白血病患儿。采用聚合酶链反应（PCR）-限制性片段长度多态性和PCR产物测序法检测CYP3A53基因型。然后用PCR法检测CYP3A5的mRNA表达。采用咪达唑仑探针法检测CYP3A酶活性，用高效液相色谱法测定DNR浓度。不同基因型患儿CYP3A5的mRNA表达水平不同，CYP3A51等位基因患儿的CYP3A酶活性高于CYP3A53等位基因患儿。此外，不同基因型患儿DNR的曲线下面积（AUC）0-24 h和AUC0-∞有显著差异，但半衰期和最大浓度无统计学差异。与正常组相比，发生心脏毒性的急性淋巴细胞白血病患儿DNR的AUC升高。CYP3A53基因多态性与CYP3A5的mRNA表达、CYP3A酶活性及DNR血药浓度密切相关，并表现出不同的药物不良反应。
