1,3-Butadiene (BD) is an important industrial and environmental chemical present in urban air and cigarette smoke, and classified as a human carcinogen. It is oxidized by cytochrome P450 to form 3,4-epoxy-1-butene (EB); EB induces point mutations at G:C and A:T base pairs in DNA. In the present work, structural analysis was performed on two stereoisomeric deoxyuridine adducts induced by EB: R- and S-N3-(2-Hydroxy-3-buten-1-yl)-2'-Deoxyuridine (1  and 2  respectively). These adducts prevent Watson-Crick base pairs, and they are anticipated to be pro-mutagenic lesions. NMR spectroscopy was utilized to determine how these adducts alter the structure and dynamics of DNA. Thermal melting studies indicated reduced stabilities for duplexes containing either adducts 1  or 2  , by 11 �C and 9 �C respectively. Structures of the R- (1  ) and S-BD-N3-dU (2  ) adducts were determined in 5'-d(GCTAGCXAGTCC)-3'�5'-d(GGACTGGCTAGC)-3' duplex, where X = R- or S- BD-N3-dU. The NOESY spectra of duplexes containing adducts 1  or 2  were similar as compared to the unmodified duplex, suggesting localized structural changes at the lesion sites. Both adducts are oriented towards 5' direction, while Ha, a' hydrogens are facing neighbor 3' adenine base. Both adducts disrupt Watson-Crick base pairing between modified X base and opposite G, but they do not affect neighbor base pairs. Supported by NIH grants R01 ES-05509, S10 RR-05805, S10 RR-025677 and NSF Grant DBI 0922862, the latter funded by the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

Structures of the <i>R</i>- and <i>S</i>-N3-(2-hydroxy-3-buten-1-yl)-2'-deoxyuridine adducts arising from 1,2-epoxy-3-butene in DNA

246th National Meeting (2013)

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Structures of the R- and S-N3-(2-hydroxy-3-buten-1-yl)-2'-deoxyuridine adducts arising from 1,2-epoxy-3-butene in DNA