三价砷甲基转移酶基因AS3MT对三氧化二砷所致APL患者砷代谢能力下降和肝脂肪变性的影响及机制研究

项目名称： 三价砷甲基转移酶基因AS3MT对三氧化二砷所致APL患者砷代谢能力下降和肝脂肪变性的影响及机制研究

项目编号： No.81500159

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 祝洪明

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 三氧化二砷(ATO)联合全反式维甲酸(ATRA)治疗急性早幼粒细胞白血病(APL)取得了突破性进展，成为APL的一线用药。但ATO的毒副作用，尤其是慢性毒性和潜在致肿瘤作用仍倍受关注。虽有研究证实应用ATO后体内无长期总砷蓄积，但有关患者体内的砷代谢和慢性毒副作用尚缺乏报道和系统研究。我们前期工作发现ATO治疗后部分患者的砷甲基化代谢能力下降，致肝脂肪变性问题较突出，与人体内无机砷甲基化代谢解毒的关键基因——三价砷甲基转移酶基因(AS3MT)的单核苷酸多态性(SNPs)相关。本研究拟在前期工作的基础上观察AS3MT基因SNPs对AS3MT酶的表达量(mRNA、酶定量)和酶功能(砷甲基化指数)变化的影响，揭示肝细胞氧化应激损伤、肝脂肪变性的机制，及其与砷甲基化能力下降之间的关系，监测砷甲基化指数判断发生肝脂肪变性的危险性，探索重组人AS3MT的保护作用，提高ATO作为APL一线用药的安全性。

中文关键词： 三氧化二砷；三价砷甲基转移酶基因；单核苷酸多态性；甲基化能力；肝脂肪变性

英文摘要： Arsenic trioxide (ATO) has gained great progress in the treatment of acute promyelocytic leukemia (APL) combined with all-trans retinoic acid, and has become front-line agent. However, the adverse effects, particularly the chronic toxicity and potential carcinogenicity caused by ATO are still the main concerns. Although studies have proved no retension of total arsenic after the cessasion of ATO, little report or systematic investigation is taken into the metabolism and chronic toxicity among patients. Our previous work showed that after the cessation of ATO, the methylation capability of some APL patients is injured, revealing a high incidence of hepatic steatosis, which was associated with the single nucleotide polymorphisms (SNPs) of arsenic (+3 oxidation state) methyltransferase gene (AS3MT), a key gene in charge of the methylation metabolism and detoxication of inorganic arsenic in human body. On the basis of previous studies, this project is aimed to survey the impact of SNPs in AS3MT on the changes of AS3MT amount (measured by mRNA and enzymes) and function (measured by the methylation index of arsenic), to discover the mechanisms of hepatotoxicity under oxidative stress, as well as the hepatic steatosis, to elucidate its relationship with injured methylation capability, to evaluate the risk of hepatic steatosis by monitoring dynamic changes in arsenic methylation index, and to assess the protective effect of recombinant human AS3MT, thus improving the safety of ATO as front-line therapy for APL.

英文关键词： arsenic trioxide;arsenic (+3 oxidation state) methyltransferase gene;single nucleotide polymorphism;methylation capability;hepatic steatosis