title: Accumulation of intact sulfur mustard in adipose tissue and toxicokinetics by chemical conversion and isotope-dilution liquid chromatography-tandem mass spectrometry.
abstract: 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.
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zong
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Yajiao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Qi
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China. xuhua-1979@163.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China. xiejwbmi@163.com.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Haidian District, 100850, Beijing, China.
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects*; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics / Q000633:toxicity; D002853:Chromatography, Liquid / Q000379:methods*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D009151:Mustard Gas / Q000493:pharmacokinetics* / Q000633:toxicity*; D011865:Radioisotope Dilution Technique; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014018:Tissue Distribution; D066007:Toxicokinetics
chemical_list: D002619:Chemical Warfare Agents; D009151:Mustard Gas
keywords: Derivatization; Intact sulfur mustard; Liquid chromatography–tandem mass spectrometry; Tissue distribution; Toxicokinetics