AS3MT基因多态性与AS2O3治疗APL患者肝毒性易感性无关联:一项单中心研究

Zeinab Joneidi, Yousef Mortazavi, Bahram Chahardouli, Shahrbano Rostami, Mohammad Vaezi, Majid Nabipour, Alireza Biglari, Ardeshir Ghavamzadeh
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引用次数: 0

摘要

背景:三氧化二砷(As2O3)是急性早幼粒细胞白血病(APL)的治疗选择。对As2O3引起的毒性具有预测价值的可能危险因素知之甚少。生物甲基化被认为是无机砷(iAs)解毒的主要途径。砷甲基转移酶(Arsenic Methyltransferase, AS3MT)是参与s -腺苷- l-蛋氨酸甲基转移到三价砷的关键酶之一,在砷解毒过程中起关键作用。hAS3MT的多态性导致酶的催化活性改变,并可能增加砷相关毒性的风险。在这项研究中,我们研究了AS3MT基因多态性(rs11191439、rs3740390和rs3740393)与As2O3治疗的APL患者肝毒性的关系。材料与方法:对140例接受As2O3治疗的APL患者进行基因分型,rs11191439采用PCR-RFLP, rs3740390和rs3740393采用四引物ARMS-PCR。PCR-RFLP和ARMS-PCR的结果通过对10%的DNA样本直接测序得到证实。使用SNPStats、SPSS和FinchTV对结果进行分析。肝毒性根据国家癌症研究所的共同毒性标准(CTC)进行分级。结果:140例患者中出现肝毒性52例(37.1%),其中ⅰ、ⅱ级肝毒性40例(28.6%),ⅲ、ⅳ级肝毒性12例(8.5%)。使用五种遗传模型评估了三种多态性与肝毒性之间的关系,发现三种研究的多态性均未与肝毒性显著相关。 讨论:我们的研究结果显示,AS3MT rs11191439、rs3740390和rs3740393多态性与APL患者的肝毒性无关。参与砷代谢的酶的遗传多态性已被证明具有种族和种族相关的差异。为了更准确地描述AS3MT基因多态性与肝毒性之间的关系,未来需要在非亚洲人群和其他种族中进行大规模研究。
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No Association of AS3MT Gene Polymorphisms with Susceptibility to Hepatotoxicity and in APL Patients Treated with AS2O3: A Single Center Study
Background: Arsenic three oxide (As2O3) is the treatment choice for acute promyelocytic leukemia (APL). Little is known about possible risk factors with predictive value for toxicity caused by As2O3. Biomethylation is considered to be a major pathway of detoxification for inorganic arsenics (iAs). Arsenic Methyltransferase (AS3MT) is one of the key enzymes involved in the transfer of a methyl group from S-adenosyl-L-methionine to trivalent arsenical and plays a critical role in arsenic detoxification. Polymorphisms in hAS3MT lead to a change in the catalytic activity of the enzyme and may increase the risk of arsenic-related toxicity. In this study, we investigated the association of the AS3MT polymorphisms (rs11191439, rs3740390, and rs3740393) genes with hepatotoxicity in APL patients treated with As2O3. Materials and Methods: Genotyping was performed in 140 adult patients with APL treated with As2O3 using PCR-RFLP for rs11191439 and tetra-primer ARMS-PCR for rs3740390 and rs3740393. The results of PCR-RFLP and ARMS-PCR were confirmed by direct sequencing of 10 % of DNA samples. The results were analyzed using SNPStats, SPSS, and FinchTV. Hepatotoxicity was graded according to the National Cancer Institute's Common Toxicity Criteria (CTC). Results: Hepatotoxicity was seen in 52 of the 140 patients (37.1%), with grades I and II hepatotoxicity in 40 (28.6%) and grades III and IV hepatotoxicity in 12 (8.5%) patients. The association between the three polymorphisms and hepatotoxicity was evaluated using five genetic models and none of the three studied polymorphisms were significantly associated with hepatotoxicity. Discussion: The results of our study showed that AS3MT rs11191439, rs3740390, and rs3740393 polymorphisms are not associated with hepatotoxicity in APL patients. Genetic polymorphisms in enzymes which are involved in arsenic metabolism have been shown to have ethnicity and race-related differences. To more precisely characterize the association between AS3MT gene polymorphism and hepatotoxicity, future large-scale studies in non-Asian populations and other ethnicities are needed.
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