Dimethylarsinothioyl glutathione as a metabolite in human multiple myeloma cell lines upon exposure to Darinaparsin.
Dimethylarsinothioyl glutathione as a metabolite in human multiple myeloma cell lines upon exposure to Darinaparsin.
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DOI：
10.1021/tx400386c
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发表时间：
2014-05-19
影响因子：
4.1
通讯作者：
Cai Y
中科院分区：
文献类型：
--
作者：
Yehiayan L;Stice S;Liu G;Matulis S;Boise LH;Cai Y
在这里，我们报道了二甲基硫代谷胱甘肽（DMMTAV(GS)）作为二甲基硫代谷胱甘肽（Darinaparsin， DMAIII(GS)）治疗人类多发性骨髓瘤（MM）细胞系的细胞提取物的代谢物的鉴定。用电感耦合等离子体质谱仪（ICP-MS）共洗脱硫和砷，在经DMAIII（GS）处理的细胞株的物种形成色谱上，发现新观察到的未知分子中有硫和砷的存在。液相色谱-电喷雾电离-质谱分析显示，在质谱和串联质谱模式下，未知峰的分子离子峰位于m/z = 443.9和466.0，对应于[DMMTAV(GS) + H]+和[DMMTAV(GS) + Na]+，以及谷氨酸损失峰314.8和甘氨酸损失峰231.1。此外，半胱氨酸和甘氨酸加合物的峰在176.9处，[C2H6AsS]+离子的峰在137.1处。用标准的DMMTAV（GS）对细胞提取物进行加峰处理，观察到未识别峰的峰面积增加。MM细胞的热失活阻止了DMMTAV（GS）的形成，提高了其通过酶促反应形成的可能性。DMAIII（GS）处理的MM细胞的形成研究揭示了DMMTAV（GS）的形成依赖于DMAIII（GS）的消耗。5mm谷胱甘肽的存在阻止了其形成，表明DMAIII（GS）的解离产物DMAIII可能是DMMTAV（GS）形成的前体。DMMTAV（GS）在酸性和中性pH条件下（pH 3.0-7.4）均可形成。此外，DMMTAV（GS）在酸性和中性pH条件下在细胞提取物中都是稳定的。当通过将多发性骨髓瘤细胞暴露于外部砷来评估毒性时，发现DMMTAV（GS）的毒性远低于DMAIII（GS）和DMMTAV，这可能是由于其在细胞中的摄取有限（分别为DMAIII（GS）和DMMTAV摄取的10%和16%）。
Here, we report the identification of dimethylarsinothioyl glutathione (DMMTAV(GS)) as a metabolite in cellular extracts of dimethyarsinous glutathione (Darinaparsin, DMAIII(GS)) treated human multiple myeloma (MM) cell lines. Co-elution of sulfur and arsenic on the inductively coupled plasma mass spectrometer (ICP-MS) indicated the presence of sulfur along with arsenic in the newly observed unidentified molecule on the speciation chromatograms of cell lines treated with DMAIII(GS). Liquid chromatography–electrospray ionization–mass spectrometry of the unknown peak in the MS and tandem MS modes revealed molecular ion peaks at m/z = 443.9 and 466.0, corresponding to [DMMTAV(GS) + H]+ and [DMMTAV(GS) + Na]+, as well as peaks at 314.8 for the loss of glutamic acid and 231.1 for the loss of glycine. In addition, peaks were observed at 176.9 corresponding to cysteine and glycine adducts and at 137.1 for the [C2H6AsS]+ ion. An increase in the peak area of the unidentified peak was observed upon spiking the cell extracts with a standard of DMMTAV(GS). Heat deactivation of MM cells prevented the formation of DMMTAV(GS) raising the possibility of its formation via an enzymatic reaction. Formation studies in DMAIII(GS) treated MM cells revealed the dependence of DMMTAV(GS) formation on the depletion of DMAIII(GS). The presence of 5 mM glutathione prevented its formation, indicating that DMAIII, a dissociation product of DMAIII(GS), is likely a precursor for the formation of DMMTAV(GS). DMMTAV(GS) was observed to form under acidic and neutral pH conditions (pH 3.0–7.4). In addition, DMMTAV(GS) was found to be stable in cell extracts at both acidic and neutral pH conditions. When assessing the toxicity by exposing multiple myeloma cells to arsenicals externally, DMMTAV(GS) was found to be much less toxic than DMAIII(GS) and DMMTAV, potentially due to its limited uptake in the cells (10 and 16% of the uptakes of DMAIII(GS) and DMMTAV, respectively).
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影响因子：
2
作者：
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通讯作者：
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影响因子：
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通讯作者：
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