Importance of monitoring arsenic methylation metabolism in acute promyelocytic leukemia patients receiving the treatment of arsenic trioxide.
Importance of monitoring arsenic methylation metabolism in acute promyelocytic leukemia patients receiving the treatment of arsenic trioxide.
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监测接受三氧化二砷治疗的急性早幼粒细胞白血病患者砷甲基化代谢的重要性
DOI：
10.1186/s40164-021-00205-6
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发表时间：
2021-02-06
影响因子：
10.9
通讯作者：
Zhu HM
中科院分区：
文献类型：
--
作者：
Zheng Y;Mao YF;Zhao HJ;Chen L;Wang LN;Zhang YX;Hu J;Li JM;Li XY;Zhu HM
三氧化二砷[ATO，溶液中的无机亚砷酸盐（iAsIII）]在急性早幼粒细胞白血病（APL）的治疗中发挥着重要作用。然而，APL患者中砷的长期不良反应（AEs）及砷的残留情况鲜有报道。在本研究中，正如我们之前所报道的，我们聚焦于完成ATO治疗的APL患者的砷甲基化代谢及其与慢性肝毒性的关系。
本研究共纳入112例初发且完成含ATO治疗的APL患者。采用高效液相色谱结合电感耦合等离子体质谱法（HPLC - ICP - MS）检测患者血浆、尿液、头发及指甲中的砷形态[iAsIII、无机砷酸盐（iAsV）及其有机代谢产物一甲基胂酸（MMA）和二甲基胂酸（DMA）]。运用聚合酶链反应法检测砷（+3氧化态）甲基转移酶（AS3MT）基因的18个单核苷酸多态性（SNPs），该基因被认为是砷甲基化的主要催化酶。
研究显示了接受ATO治疗期间及治疗后的APL患者体内砷的代谢模式，包括总砷（TAs）及四种砷形态。停止ATO治疗6个月后，TAs降至正常水平。但砷形态分析表明，患者尿液（40.08% 对比 1.94%，P < 0.001）、头发（29.25% 对比 13.29%，P = 0.002）和指甲（30.21% 对比 13.64%，P = 0.003）中的iAsIII比例显著高于健康对照组，这表明ATO治疗后患者砷甲基化代谢能力下降。慢性肝功能不全患者（0.14对比0.28，P = 0.047）和肝脂肪变性患者（0.19对比0.3，P = 0.027）的尿一级甲基化指数（PMI）均显著降低，提示砷甲基化不足可能与慢性肝脏疾病有关。AS3MT基因的两个SNPs（A9749G和A27215G）与尿二级甲基化指数（SMI）受损相关。
对砷形态的长期随访表明，停止ATO治疗后，APL患者砷甲基化代谢能力下降，且可能与慢性肝脏疾病存在关联。尿PMI可作为ATO慢性不良反应的监测指标，在确定ATO剂量时应考虑AS3MT基因的SNPs。
BackgroundArsenic trioxide [ATO, inorganic arsenite (iAsIII) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL). However, the long-term adverse effects (AEs) and the retention of arsenic among APL patients are rarely reported. In this study, we focused on arsenic methylation metabolism and its relationship with chronic hepatic toxicity, as we previously reported, among APL patients who had finished the treatment of ATO.MethodsA total of 112 de novo APL patients who had completed the ATO-containing treatment were enrolled in the study. Arsenic species [iAsIII, inorganic arsenate (iAsV), and their organic metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] in patients’ plasma, urine, hair and nails were detected by high-performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Eighteen single nucleotide polymorphisms (SNPs) of the arsenic (+ 3 oxidative state) methylation transferase (AS3MT) gene, which was known as the main catalyzer for arsenic methylation, were tested with the polymerase chain reaction method.ResultsThe study showed the metabolic pattern of arsenic in APL patients undergoing and after the treatment of ATO, in terms of total arsenic (TAs) and four species of arsenic. TAs decreased to normal after 6 months since cessation of ATO. But the arsenic speciation demonstrated significantly higher portion of iAsIIIin patient’s urine (40.08% vs. 1.94%,P< 0.001), hair (29.25% vs. 13.29%,P= 0.002) and nails (30.21% vs. 13.64%,P= 0.003) than the healthy controls’, indicating a decreased capacity of arsenic methylation metabolism after the treatment of ATO. Urine primary methylation index (PMI) was significantly lower in patients with both chronic liver dysfunction (0.14 vs. 0.28,P= 0.047) and hepatic steatosis (0.19 vs. 0.3,P= 0.027), suggesting that insufficient methylation of arsenic might be related to chronic liver disorders. Two SNPs (A9749G and A27215G) of theAS3MTgene were associated with impaired urine secondary methylation index (SMI).ConclusionsThe long-term follow-up of arsenic speciation indicated a decreased arsenic methylation metabolism and a probable relationship with chronic hepatic disorders among APL patients after the cessation of ATO. Urine PMI could be a monitoring index for chronic AEs of ATO, and the SNPs ofAS3MTgene should be considered when determining the dosage of ATO.
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