Abstract
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 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).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 of AS3MT gene should be considered when determining the dosage of ATO.
Highlights
Arsenic trioxide [ATO, inorganic arsenite (iAsIII) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL)
Urine primary meth‐ ylation index (PMI) could be a monitoring index for chronic adverse effects (AEs) of ATO, and the single nucleotide polymorphisms (SNPs) of AS3MT gene should be considered when deter‐ mining the dosage of ATO
The 112 patients were divided into different groups according to their time intervals between the cessation of ATO and the arsenic test, namely off ATO 0–6 months (0–6 months, 8 cases), 7–2 months (10 cases), 1 –2 years
Summary
Arsenic trioxide [ATO, inorganic arsenite (iAsIII) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL). The long-term adverse effects (AEs) and the retention of arsenic among APL patients are rarely reported. 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. Arsenic trioxide (ATO) has achieved great success in the treatment of acute promyelocytic leukemia (APL) in combination with all-trans retinoic acid (ATRA), improving the rate of complete remission (CR) up to 92% or higher, [1,2,3] and the long-term overall survival (OS) reaching 87–97% [4,5,6,7,8]. The retention and metabolism of ATO in patients are unclear, and the potential long-term arsenic intoxication and secondary carcinogenesis of ATO are rarely reported. Inorganic arsenics are methylated in the hepatocytes into less toxic metabolites, such as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), and excreted via urine. Other SNPs on the introns (including G12390C, T12590C, T35587C, T14215C, G35991A and so on) were reported to be associated with elevated DMA or MMA in the urine [13,14,15,16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
