Monomethylarsonous acid binds to Cys-104? and Cys-112? of hemoglobin in acute promyelocytic leukemia patients treated with arsenic trioxide

作者：Gao, Chunlu; Lin, Liwang; Li, Jing; Wu, Mengliang; Lv, Jian; Tian, Shuo; Hai, Xin^*

来源：Toxicology Letters, 2023, 380: 31-39.

DOI：10.1016/j.toxlet.2023.04.001

• Arsenic trioxide
• Acute promyelocytic leukemia
• Monomethylarsonous acid
• Hemoglobin
• Erythrocytes

Arsenic trioxide (As2O3) has prominent effect in treating acute promyelocytic leukemia (APL). Identification of arsenic-binding proteins has gained attention for their important biological functions. However, none has been published concerning the binding mechanism of arsenic with hemoglobin (Hb) in APL patients after treatment of As2O3. The present study discloses the binding sites of arsenic on Hb in APL patients. Concentrations of inorganic arsenic (iAs), monomethyl arsenic (MMA), and dimethyl arsenic (DMA) in erythrocytes of APL patients were quantified using HPLC-inductively coupled plasma-mass spectroscopy (HPLC-ICP-MS). Hb-bound arsenic was identified by size-exclusion chromatography ICP-MS. The binding sites of arsenic on Hb were determined by mass spectrometry (MS). The concentration trend of arsenic species in erythrocytes of 9 APL patients treated with As2O3 was iAs>MMA>DMA, and MMA was the predominant methylated arsenic metabolite. Size-exclusion chromatography separation of free and protein-bound arsenic by simultaneous monitoring of 57Fe and 75As demonstrated the presence of Hb-bound arsenic. MS information suggested monomethylarsonous (MMAIII) was the dominant arsenic bound to Hb, and further identified that Cys-104 alpha and Cys-112 beta were two binding sites of MMAIII in Hb. MMAIII binding to Cys-104 alpha and Cys-112 beta was responsible for arsenic accumulation in erythro-cytes of APL patients. This interaction may contribute to understand the therapeutic effect of As2O3 as an anticancer drug and its toxicity on APL patients.

• 单位
  1; 哈尔滨医科大学