Accumulation of intact sulfur mustard in adipose tissue and toxicokinetics by chemical conversion and isotope-dilution liquid chromatography–tandem mass spectrometry
Accumulation of intact sulfur mustard in adipose tissue and toxicokinetics by chemical conversion and isotope-dilution liquid chromatography–tandem mass spectrometry
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DOI：
10.1007/s00204-016-1774-z
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发表时间：
2016-06
影响因子：
6.1
通讯作者：
Bin Xu;Cheng Zong;Yajiao Zhang;Tianhong Zhang;Xiaoying Wang;M. Qi;Jianfeng Wu;Lei Guo;
中科院分区：
文献类型：
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作者：
Bin Xu;Cheng Zong;Yajiao Zhang;Tianhong Zhang;Xiaoying Wang;M. Qi;Jianfeng Wu;Lei Guo;
芥子气（SM）是一种强效发泡剂，也是危害最大的化学战剂之一。SM中毒的机制至今尚未完全阐明，也没有有效的解毒剂或特异性治疗方法。研究SM的毒代动力学和组织分布有助于了解SM的毒性，为SM中毒的预处理和治疗提供理论依据。但是，由于SM的高反应性和生物医学样品分析的困难，完整SM在体内的代谢轨迹或命运仍然不清楚，并且没有足够的实验数据来阐明。本文建立了一种灵敏的同位素稀释LC-MS/MS结合化学转化检测和定量血液或组织中完整SM的方法。通过将高活性的SM转化为稳定的衍生物，准确测定生物样品中完整SM的真实的浓度。大鼠静脉（10 mg/kg）或皮肤给药（1、3和10 mg/kg）后，通过新方法成功描述了完整SM的毒代动力学和组织分布研究。皮肤暴露实验中SM血药浓度在30-60 min达高峰，血药浓度明显高于文献报道，血药平均滞留时间延长至1 ~ 1.5 h。在脂肪组织（包括肾周脂肪、附睾脂肪、皮下脂肪和棕色脂肪）中观察到完整SM的显著蓄积，其中SM的浓度至少是皮肤暴露大鼠非脂肪组织中SM浓度的15倍。SM在体脂肪中的回收率计算为生物可利用SM的3.3%（皮肤暴露后的生物利用度评估为16%）。因此，脂肪组织是重要的SM分布和毒性，这可能开辟了一个新的模式，无论是预防和治疗SM暴露。
Sulfur mustard (SM) is a powerful vesicant and one of the most harmful chemical warfare agents. Although having been studied for a long time, it is still difficult to fully elucidate the mechanisms of SM poisoning, and there is no effective antidote or specific treatment for SM injury. The investigations on toxicokinetics and tissue distribution of SM will help to understand its toxicity and provide a theoretical basis for pretreatment and therapy of SM poisoning. But the metabolic trajectory or fate of intact SM in vivo remains unclear, and there are insufficient experimental data to elucidate, due to its high reactivity and difficulty in biomedical sample analysis. In this paper, a sensitive method for the detection and quantification of intact SM in blood or tissues using isotope-dilution LC–MS/MS coupled with chemical conversion was developed. By transforming highly reactive SM into stable derivative product, the real concentration of intact SM in biological samples was obtained accurately. The toxicokinetics and tissue distribution studies of intact SM in rats were successfully profiled by the novel method after intravenous (10 mg/kg) or cutaneous administration (1, 3 and 10 mg/kg). The SM level in blood with peak time at 30–60 min determined in cutaneous exposure experiment was found much higher than previously reported, and the mean residence time in blood extended to 1–1.5 h. A significant accumulation of intact SM was observed in adipose tissues, including the perirenal fat, epididymal fat, subcutaneous fat and brown fat, in which the concentrations of SM were at least 15 times greater than those in non-adipose tissues in cutaneous exposed rats. The recovery of SM in body fat was calculated as 3.3 % of bioavailable SM (the bioavailability after cutaneous exposure was evaluated as 16 %). Thus, the adipose tissue was important for SM distribution and toxicity, which may pioneer a new model for both the prevention and treatment of SM exposure.