Importance of monitoring arsenic methylation metabolism in acute promyelocytic leukemia patients receiving the treatment of arsenic trioxide

Abstract

Background Arsenic 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. Methods A 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. Results The 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 iAsIII in 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 the AS3MT gene were associated with impaired urine secondary methylation index (SMI). Conclusions The 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 of AS3MT gene should be considered when determining the dosage of ATO.

Urine Self-Sampling Kit Combined with an Automated Preparation-Sampler Device for Convenient and Reliable Analysis of Arsenic Metabolites by HPLC–ICPMS

“…The subsequent fluid handling procedures are performed under anaerobic conditions by program control edited in sscom 5.13.1 software as follows. An appropriate amount of 0.02 mol L –1 acetic acid is taken and added to the SV, and the planet gears are rotated for 1 min to mix the acetic acid and the urine in order to dilute the urine to the appropriate concentration (each arsenic species at <20 μg L –1 , minimum dilution of urine at 4-fold). , This process not only reduces the potential adsorption of the target on the surface of the sample container but also reduces the concentration of interferents in the matrix and increases the solubility of inorganic salts to prevent instrument contamination. Afterward, 1 mL of diluted urine is filtered through an online filter to remove large particle impurities from the urine and injected into the HPLC.…”

“…Arsenic is a global environmental contaminant that puts the health of millions of people around the world at risk due to the increased intake of inorganic arsenic from contaminated drinking water. , It is a recognized human carcinogen, but its toxicity varies greatly depending on arsenic species. , Methylated trivalent arsenic species (MMA III and DMA III ) are more cytotoxic and genotoxic than their pentavalent counterparts (MMA V and DMA V ) and approach or exceed inorganic arsenic species (iAs III and iAs V ). , Studies have shown that biomethylation is the main pathway of inorganic arsenic metabolism in the human body, and thus speciation analysis of metabolites is essential to better understand the transport and transformation of arsenic in the human body and its impact on health. , Urine is often the preferred sample for drug metabolism testing because it is easy to collect and typically contains a higher concentration of drugs and metabolites than blood, which can make the test easier to perform. − In the clinical application of As 2 O 3 , urinary arsenic is an important biomarker for the evaluation of arsenic metabolism and toxicity. − However, MMA III and DMA III are significantly less stable than other arsenic species in urine, which can be rapidly oxidized to MMA V and DMA V in the presence of air . In addition, many studies on urinary arsenic species involve collecting urine samples from people in areas with high levels of arsenic in crops and drinking water and then transporting them to a laboratory for speciation analysis of arsenic. − Therefore, the development of a method that can be used for urine self-sampling (USS) at home and improve the stability of MMA III and DMA III in urine is of great significance for ensuring the accuracy of arsenic speciation analysis and studying the roles of MMA III and DMA III in disease occurrence and progression.…”

Atomic Spectrometry Update: review of advances in elemental speciation

“…In a third study, the researchers focused on the As methylation metabolism and its relationship with chronic hepatic toxicity among APL patients who had finished treatment with As 2 O 3 . 79 A total of 112 de novo APL patients who had completed the As 2 O 3 treatment were enrolled in the study. The As species As III , As V , MMA V and DMA V in patients’ plasma, urine, hair and nails were determined by HPLC-ICP-MS. Eighteen single nucleotide polymorphisms (SNPs) of the As III methylation transferase (AS3MT) gene, which was known as the main catalyser for As methylation, were tested using PCR.…”