Arsenic (+3 oxidation state) methyltransferase (AS3MT) is a key enzyme responsible for arsenic metabolism in humans, which facilitates conversion of arsenic trioxide (As₂O₃) to more reactive metabolites such as monomethylarsonous acid (MMA^III) and dimethylarsinous acid (DMA^III). However, it is unclear whether the biotransformation of arsenic by AS3MT contributes to the promotion of acute promyelocytic leukemia (APL) therapy. In order to understand the probable role of AS3MT in APL patients, we evaluated the effects of arsenite (iAs^III) and three mixed arsenicals (i.e., iAs^III, MMA^III and DMA^III, to mimic active arsenic species in the blood) on NB4 cell differentiation and apoptosis. Although the mixed arsenicals exhibited about 2 fold less effect on the induction of NB4 cell differentiation and PML-RARα fusion protein degradation, they showed 5 times stronger ability to induce apoptosis when compared with iAs^III. More importantly, the proliferation of NB4 cells was significantly (p < 0.05) inhibited in a transwell system co-cultured with AS3MT-transfected HepG2 cells after exposure to iAs^III, suggesting that the generation of methylated metabolites restrained cell proliferation. These findings indicate that the therapeutic efficacy of As₂O₃ (i.e., iAs^III) in APL patients is probably associated with the production of methylated arsenic metabolites (i.e., MMA^III and DMA^III) by AS3MT.

中文翻译：

---

砷（+3氧化态）甲基转移酶在砷介导的APL治疗中的作用：一项体外研究†

砷（+3氧化态）甲基转移酶（AS3MT）是负责人体中砷代谢的关键酶，可促进三氧化二砷（As ₂ O ₃）转化为更具反应性的代谢物，例如单甲基ar酸（MMA ^III）和二甲基ar酸（ DMA ^III）。但是，尚不清楚AS3MT对砷的生物转化是否有助于促进急性早幼粒细胞白血病（APL）治疗。为了了解AS3MT在APL患者中的可能作用，我们评估了亚砷酸盐（iAs ^III）和三种混合砷（即iAs ^III，MMA ^III和DMA ^{III）的作用}，以模拟血液中的活性砷物质）对NB4细胞的分化和凋亡。尽管混合砷对NB4细胞分化和PML-RARα融合蛋白降解的诱导作用降低了约2倍，但与iAs ^III相比，它们的诱导凋亡能力强5倍。更重要的是，暴露于iAs ^III后，在与AS3MT转染的HepG2细胞共培养的Transwell系统中，NB4细胞的增殖受到显着抑制（p <0.05），这表明甲基化代谢产物的产生抑制了细胞增殖。这些发现表明，As ₂ O ₃（即，APL患者中的iAs ^III）可能与AS3MT产生甲基化砷代谢产物（即MMA ^III和DMA ^III）有关。