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Regioselective formation of acrolein-derived cyclic 1,N(2)-propanodeoxyguanosine adducts mediated by amino acids, proteins, and cell lysates.
- Source :
-
Chemical research in toxicology [Chem Res Toxicol] 2012 Sep 17; Vol. 25 (9), pp. 1921-8. Date of Electronic Publication: 2012 Aug 14. - Publication Year :
- 2012
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Abstract
- Acrolein (Acr) is a major component in cigarette smoke and a ubiquitous environmental pollutant. It is also formed as a product of lipid peroxidation. Following ring closure via the Michael addition, Acr modifies deoxyguanosine (dG) in DNA by forming cyclic 1,N(2)-propanodeoxyguanosine adducts (OHPdG). The reactions of Acr with dG yield, depending on the direction of ring closure, two regioisomers, α- and γ-OHPdG, in approximately equal amounts. However, previous (32)P-postlabeling studies showed that the γ isomers were detected predominantly in the DNA of rodent and human tissues. Because of the potential differential biological activity of the isomeric OHPdG adducts, it is important to confirm and study the chemical basis of the regioselective formation of γ isomers in vivo. In this study, it is confirmed that γ-OHPdG adducts are indeed the major isomers formed in vivo as evidenced by a LC-MS/MS method specifically developed for Acr-derived dG adducts. Furthermore, we have shown that the formation of γ-isomers is increased in the presence of amino-containing compounds, including amino acids, proteins, and cell lysates. A product of Acr and arginine that appears to mediate the regioselective formation of γ isomers was identified, but its structure was not fully characterized due to its instability. This study demonstrates that intracellular amino-containing compounds may influence the regiochemistry of the formation of OHPdG adducts and reveals a mechanism for the preferential formation of γ-OHPdG by Acr in vivo.
- Subjects :
- Animals
Borohydrides chemistry
Cell Line
Chromatography, High Pressure Liquid
DNA chemistry
Deoxyguanosine chemistry
Histones chemistry
Humans
Liver chemistry
Oxidation-Reduction
Proteins metabolism
Rats
Serum Albumin, Bovine chemistry
Smoking
Spermidine chemistry
Stereoisomerism
Acrolein chemistry
Amino Acids chemistry
DNA Adducts chemistry
Deoxyguanosine analogs & derivatives
Proteins chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-5010
- Volume :
- 25
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Chemical research in toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 22853434
- Full Text :
- https://doi.org/10.1021/tx3002252