Abstract
Polymorphisms in arsenic (+ 3 oxidation state) methyltransferase (AS3MT) have been shown to be related to interindividual variations in arsenic metabolism and to influence adverse health effects in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (As2O3). The occurrence of hyperleukocytosis with As2O3 treatment seriously affects the early survival rate of APL patients, but no definite explanation for such a complication has been clearly established. To clarify the causes of this situation, AS3MT polymorphisms 14215 (rs3740390), 14458 (rs11191439), 27215 (rs11191446), and 35991 (rs10748835) and profiles of plasma arsenic metabolites were evaluated in a group of 54 newly diagnosed APL patients treated with single-agent As2O3. High-performance liquid chromatography–hydride generation-atomic fluorescence spectrometry (HPLC–HG-AFS) was used to determine the concentrations of plasma arsenic metabolites. Plasma arsenic methylation metabolism capacity was evaluated by the percentage of inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), primary methylation index (PMI, MMA/iAs), and secondary methylation index (SMI, DMA/MMA). The results showed that APL patients who developed hyperleukocytosis had a higher plasma iAs%, but a lower MMA% and PMI than those who did not develop hyperleukocytosis during As2O3 treatment. In addition, patients with the AS3MT 14215 (rs3740390) CC genotype had significantly higher plasma iAs% and incidence of hyperleukocytosis, but lower PMI than patients with the CT + TT genotype. Conversely, we did not observe statistically significant associations between the occurrence of hyperleukocytosis and AS3MT 14458 (rs11191439), 27215 (rs11191446), and 35991 (rs10748835) polymorphisms in our study subjects. These results indicated that AS3MT 14215 (rs3740390) might be used as an indicator for predicting the occurrence of hyperleukocytosis in APL patients treated with As2O3.
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Acknowledgements
This work was financially supported by grants from the National Natural Science Foundation of China (Grant Nos. 81700151, 81430088), Heilongjiang Province Natural Science Foundation for Excellent Youths (Grant No. JJ2019YX0862), Heilongjiang Province Natural Science Foundation (Grant No. QC2015119), Advanced Programs of Returned Overseas Chinese Scholars, Heilongjiang Human Resources and Social Security Bureau (Grant No. 108) and Heilongjiang Postdoctoral Special Program (Grant No. LBH-TZ16).
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W-SL wrote the manuscript. W-SL, JL and X-YW contributed to data collection and DNA sample preparation of subjects. Y-MZ performed the statistical analysis. X-MY performed the molecular characterization of subjects. W-SL, Q-LZ and Z-QW performed the determination of arsenic metabolites. J-ML helped with the medical management of the study patients. XH and JZ designed the study, analyzed and discussed the data, and critically revised the manuscript. All authors have approved the final manuscript.
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Liu, WS., Wang, XY., Lu, J. et al. Polymorphisms in arsenic (+ 3 oxidation state) methyltransferase (AS3MT) predict the occurrence of hyperleukocytosis and arsenic metabolism in APL patients treated with As2O3. Arch Toxicol 94, 1203–1213 (2020). https://doi.org/10.1007/s00204-020-02686-6
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DOI: https://doi.org/10.1007/s00204-020-02686-6