化学
鸟嘌呤
加合物
脱氧鸟苷
DNA
DNA加合物
DNA损伤
DNA氧化
硫芥
烷基化
色谱法
串联质谱法
尿
质谱法
生物化学
核苷酸
有机化学
毒性
基因
催化作用
作者
Haijiang Wu,Yajiao Zhang,Hua Xu,Bin Xu,Jia Chen,Lei Guo,Liu Q,Jianwei Xie
标识
DOI:10.1021/acs.chemrestox.3c00135
摘要
Alkylation reagents, represented by sulfur mustard (SM), can damage DNA molecules directly as well as lead to oxidative stress, causing DNA lesions indirectly. Correspondingly, two types of biomarkers including alkylated DNA adducts and oxidative DNA adducts are commonly involved in the research of DNA damage evaluation caused by these agents. However, the correlations and differences of the occurrence, duration, severity, and traceability between alkylation and oxidation lesions on the DNA molecular level reflected by these two types of biomarkers have not been systematically studied. A simultaneous determination method for four alkylated DNA adducts, i.e., N7-(2-hydroxyethylthioethyl)2′-guanine (N7-HETEG), O6-(2-hydroxyethylthioethyl)-2′-guanine (O6-HETEG), N3-(2-hydroxyethylthioethyl)-2′-adenine (N3-HETEA), and bis(2-ethyl-N7-guanine)thioether (Bis-G), and the oxidative adduct 8-hydroxy-2′-deoxyguanosine (8-OH-dG) in urine samples by isotope-dilution high-performance liquid chromatography-tandem mass spectrometry (ID-HPLC-MS/MS) was built with a lower limit of detection of 0.02 ng/mL (except Bis-G, 0.05 ng/mL) and a recovery of 79–111%. The profile of these adducts was simultaneously monitored in urine samples after SD rats’ dermal exposure to SM in three dose levels (1, 3, and 10 mg/kg). The time–effect and dose–effect experiments revealed that when exposed to SM, DNA alkylation lesions would happen earlier than those of oxidation. For the two types of biomarkers, alkylated DNA adducts showed an obvious dose–effect relationship and could be used as internal exposure dose and effect biomarkers, while 8-OH-dG did not show a correlation with exposure dose, demonstrating that it was more suitable as a biomarker for DNA oxidative lesions but not an indicator for the extent of cytotoxicity and internal exposure.
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