Simultaneous determination of sulfur mustard and related oxidation products by isotope-dilution LC-MS/MS method coupled with a chemical conversion.
Sulfur mustard (SM) is a highly reactive alkylating vesicant with high toxicity and complicated metabolism, the in vivo profile of its oxidation metabolism is not still fully known and urgently needs to be clarified well. In this work, an isotope-dilution high performance liquid chromatography-tandem mass spectrometric method coupled with chemical conversion was developed for the simultaneous quantification of SM and its oxidation products, i.e., mustard sulfoxide (SMO) and mustard sulfone (SMO2). The accurate measurement of SM and its oxidation products with high reaction activity was achived via the method of chemical conversion of 2-(3,5-bis(mercaptomethyl)phenoxy) acetic acid into stable derivative products. Method validation was performed in whole blood matrix, the linear range of the method was between 0.2 and 1000μg/L with correlation coefficients (r(2))>0.99, and the lower limits of quantification for SM, SMO and SMO2 were 1, 1, 0.2μg/L, respectively. The validated method was successfully applied to a toxicokinetics research of SM and its oxidation products after SM dermal exposed rats in a single dose. All three target analytes were found in whole blood samples from poisoned rats, and significant time-dependent responses were also observed. Among them, SMO2 with relatively high toxicity was identified and quantified in vivo for the first time, while SMO was the major product in whole blood and some of them continued to be oxidized to SMO2in vivo. These results give a direct experimental evidence to support that a large amount of SM is converted into the corresponding SMO and SMO2, and these oxidation products might cause potential combined toxic effects.
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, Beijing 100850, China.
Meiling
M
Qi
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, Beijing 100850, China.
Bin
B
Xu
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, Beijing 100850, China.
Jianfeng
J
Wu
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, Beijing 100850, China.
Yajiao
Y
Zhang
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, Beijing 100850, China.
Cheng
C
Zong
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, Beijing 100850, China.
Jia
J
Chen
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, Beijing 100850, China.
Lei
L
Guo
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, Beijing 100850, China. Electronic address: xiejw@bmi.ac.cn.
Jianwei
J
Xie
D000818:Animals; D002619:Chemical Warfare Agents / Q000032:analysis / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D057230:Limit of Detection; D008297:Male; D009151:Mustard Gas / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics; D013454:Sulfoxides / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry / Q000379:methods*
D002619:Chemical Warfare Agents; D013450:Sulfones; D013454:Sulfoxides; D009151:Mustard Gas
Chemical conversion; HPLC–MS/MS; Mustard sulfone; Mustard sulfoxide; Sulfur mustard; Toxicokinetics; Whole blood