Wang Zhongwen, Zhou Jin, Lu Xiufen, Gong Zhilong, Le X Chris
Department of Public Health Sciences, University of Alberta, Edmonton, Alberta, T6G 2G3, Canada.
Chem Res Toxicol. 2004 Jan;17(1):95-103. doi: 10.1021/tx0341714.
Arsenic has been used successfully in clinical trials for treating acute promyelocytic leukemia (APL). Although sublethal doses of inorganic arsenic are used, little is known about the pharmacokinetics and metabolism of the high levels of arsenic in APL patients. To fill this important gap, this study describes the speciation of arsenic in urine from four APL patients treated with arsenic. Each patient was injected daily with an arsenite (As(III)) solution that contained 10 mg of As(2)O(3) precursor. Speciation analysis of the patient urine samples collected consecutively for 48 h, encompassing two intravenous injections of arsenic, revealed the presence of monomethylarsonous acid (MMA(III)), dimethylarsinous acid (DMA(III)), monomethylarsonic acid (MMA(V)), and dimethylarsinic acid (DMA(V)). The intermediate methyl arsenic metabolites, MMA(III) and DMA(III), were detected in most urine samples from all of the patients when a preservative, diethyldithiocarbomate, was added to the urine samples to stabilize these trivalent arsenic species. The major arsenic species detected in the urine samples from the patients were As(III), MMA(V), and DMA(V), accounting for >95% of the total arsenic excreted. The relative proportions of As(III), As(V), MMA(V), and DMA(V) in urine samples collected 24 h after the injections of As(III) were 27.6 +/- 6.1, 2.8 +/- 2.0, 22.8 +/- 8.1, and 43.7 +/- 13.3%, respectively. The relatively lower fraction of the methylated arsenic species in these APL patients under arsenic treatment as compared with that from the general population exposed to much lower levels of arsenic suggests that the high levels of As(III) inhibit the methylation of arsenic (inhibits the formation of methyl arsenic metabolites). The arsenic species excreted into the urine accounted for 32-65% of the total arsenic injected. These results suggest that other pathways of excretion, such as through the bile, may play an important role in eliminating (removing) arsenic from the human body when challenged by high levels of As(III).
砷已在治疗急性早幼粒细胞白血病（APL）的临床试验中取得成功。尽管使用的是亚致死剂量的无机砷，但对于APL患者体内高剂量砷的药代动力学和代谢情况却知之甚少。为填补这一重要空白，本研究描述了4例接受砷治疗的APL患者尿液中砷的形态。每位患者每天注射含10 mg As₂O₃前体的亚砷酸盐（As(III)）溶液。对连续48小时收集的患者尿液样本进行形态分析，涵盖两次静脉注射砷，结果显示存在一甲基亚砷酸（MMA(III)）、二甲基亚砷酸（DMA(III)）、一甲基砷酸（MMA(V)）和二甲基砷酸（DMA(V)）。当向尿液样本中添加防腐剂二乙基二硫代氨基甲酸盐以稳定这些三价砷形态时，在所有患者的大多数尿液样本中均检测到中间甲基砷代谢物MMA(III)和DMA(III)。在患者尿液样本中检测到的主要砷形态为As(III)、MMA(V)和DMA(V)，占总排泄砷的95%以上。注射As(III)后24小时收集的尿液样本中，As(III)、As(V)、MMA(V)和DMA(V)的相对比例分别为27.6±6.1%、2.8±2.0%、22.8±8.1%和43.7±13.3%。与暴露于低得多的砷水平的普通人群相比，这些接受砷治疗的APL患者体内甲基化砷形态的比例相对较低，这表明高剂量的As(III)会抑制砷的甲基化（抑制甲基砷代谢物的形成）。排泄到尿液中的砷占注射总砷量的32 - 65%。这些结果表明，当受到高剂量As(III)挑战时，其他排泄途径，如通过胆汁排泄，可能在人体消除（去除）砷方面发挥重要作用。
