Identification of a Fused-Ring 2′-Deoxyadenosine Adduct Formed in Human Cells Incubated with 1-Chloro-3-buten-2-one, a Potential Reactive Metabolite of 1,3-Butadiene
| Autor: | Jing An, Xinyu Zhang, Fang-Mao Zeng, Cong Kong, Yingxin Yu, Ling-Yan Liu, Adnan A. Elfarra, Jin Zheng |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Stereochemistry Metabolite 010501 environmental sciences Toxicology medicine.disease_cause 01 natural sciences Adduct DNA Adducts 03 medical and health sciences chemistry.chemical_compound Butadienes medicine Animals Humans Reactivity (chemistry) Carcinogen 0105 earth and related environmental sciences Deoxyadenosines Molecular Structure 2'-deoxyadenosine 1 3-Butadiene DNA Hep G2 Cells General Medicine Butanones In vitro 030104 developmental biology chemistry Cattle Genotoxicity |
| Zdroj: | Chemical Research in Toxicology. 29:1041-1050 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/acs.chemrestox.6b00095 |
| Popis: | 1-Chloro-3-buten-2-one (CBO) is an in vitro metabolite of 1,3-butadiene (BD), a carcinogenic air pollutant. CBO exhibited potent cytotoxicity and genotoxicity that have been attributed in part to its reactivity toward DNA. Previously, we have characterized the CBO adducts with 2'-deoxycytidine and 2'-deoxyguanosine. In the present study, we report on the reaction of CBO with 2'-deoxyadenosine (dA) under in vitro physiological conditions (pH 7.4, 37 °C). We used the synthesized standards and their decomposition and acid-hydrolysis products to characterize the CBO-DNA adducts formed in human cells. The fused-ring dA adducts (dA-1 and dA-2) were readily synthesized and were structurally characterized as 1,N(6)-(1-hydroxy-1-hydroxymethylpropan-1,3-diyl)-2'-deoxyadenosine and 1,N(6)-(1-hydroxy-1-chloromethylpropan-1,3-diyl)-2'-deoxyadenosine, respectively. dA-1 exhibited a half-life of 16.0 ± 0.7 h and decomposed to dA at pH 7.4 and 37 °C. At similar conditions, dA-2 decomposed to dA-1 and dA, and had a half-life of 0.9 ± 0.1 h. These results provide strong evidence for dA-1 being a degradation product of dA-2. dA-1 is formed by replacement of the chlorine atom of dA-2 by a hydroxyl group. The slow decomposition of dA-1 to dA, along with the detection of hydroxymethyl vinyl ketone (HMVK) as another degradation product, suggested equilibrium between dA-1 and a ring-opened carbonyl-containing intermediate that undergoes a retro-Michael reaction to yield dA and HMVK. Acid hydrolysis of dA-1 and dA-2 yielded the corresponding deribosylated products A-1D and A-2D, respectively. In the acid-hydrolyzed reaction mixture of CBO with calf thymus DNA, both A-1D and A-2D could be detected; however, the amount of A-2D was significantly larger than that of A-1D. Interestingly, only A-2D could be detected by LC-MS analysis of acid-hydrolyzed DNA from cells incubated with CBO, suggesting that dA-2 was stable in DNA and thus may play an important role in the genotoxicity and carcinogenicity of BD. In addition, A-2D could be developed as a biomarker of CBO formation in human cells. |
| Databáze: | OpenAIRE |
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