TY - JOUR
T1 - N 6 -(2-Deoxy- d - Erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5- N-(2-hydroxy-3-buten-1-yl)-formamidopyrimidine Adducts of 1,3-Butadiene
T2 - Synthesis, Structural Identification, and Detection in Human Cells
AU - Groehler, Arnold S.
AU - Najjar, Dominic
AU - Pujari, Suresh S.
AU - Sangaraju, Dewakar
AU - Tretyakova, Natalia Y.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/9/17
Y1 - 2018/9/17
N2 - 1,3-Butadiene (BD) is an environmental and occupational toxicant classified as a human carcinogen. BD is metabolically activated by cytochrome P450 monooxygenases to 3,4-epoxy-1-butene (EB), which alkylates DNA to form a range of nucleobase adducts. Among these, the most abundant are the hydrolytically labile N7-guanine adducts such as N7-(2-hydroxy-3-buten-1-yl)-guanine (N7-EB-dG). We now report that N7-EB-dG can be converted to the corresponding ring open N 6 -(2-deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N-(2-hydroxy-3-buten-1-yl)-formamidopyrimidine (EB-Fapy-dG) adducts. EB-Fapy-dG lesions were detected in EB-treated calf thymus DNA and in EB-treated mammalian cells using quantitative isotope dilution nanoLC-ESI + -MS/MS. EB-Fapy-dG adduct formation in EB-treated calf thymus DNA was concentration dependent and was greatly accelerated at an increased pH. EB-FAPy-dG adduct amounts were 2-fold higher in base excision repair-deficient NEIL1 -/- mouse embryonic fibroblasts (MEF) as compared to isogenic controls (NEIL1 +/+ ), suggesting that this lesion may be a substrate for NEIL1. Furthermore, NEIL1 -/- cells were sensitized to EB treatment as compared to NEIL1 +/+ fibroblasts. Overall, our results indicate that ring-opened EB-FAPy-dG adducts form under physiological conditions, prompting future studies to determine their contributions to genotoxicity and mutagenicity of BD.
AB - 1,3-Butadiene (BD) is an environmental and occupational toxicant classified as a human carcinogen. BD is metabolically activated by cytochrome P450 monooxygenases to 3,4-epoxy-1-butene (EB), which alkylates DNA to form a range of nucleobase adducts. Among these, the most abundant are the hydrolytically labile N7-guanine adducts such as N7-(2-hydroxy-3-buten-1-yl)-guanine (N7-EB-dG). We now report that N7-EB-dG can be converted to the corresponding ring open N 6 -(2-deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N-(2-hydroxy-3-buten-1-yl)-formamidopyrimidine (EB-Fapy-dG) adducts. EB-Fapy-dG lesions were detected in EB-treated calf thymus DNA and in EB-treated mammalian cells using quantitative isotope dilution nanoLC-ESI + -MS/MS. EB-Fapy-dG adduct formation in EB-treated calf thymus DNA was concentration dependent and was greatly accelerated at an increased pH. EB-FAPy-dG adduct amounts were 2-fold higher in base excision repair-deficient NEIL1 -/- mouse embryonic fibroblasts (MEF) as compared to isogenic controls (NEIL1 +/+ ), suggesting that this lesion may be a substrate for NEIL1. Furthermore, NEIL1 -/- cells were sensitized to EB treatment as compared to NEIL1 +/+ fibroblasts. Overall, our results indicate that ring-opened EB-FAPy-dG adducts form under physiological conditions, prompting future studies to determine their contributions to genotoxicity and mutagenicity of BD.
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U2 - 10.1021/acs.chemrestox.8b00123
DO - 10.1021/acs.chemrestox.8b00123
M3 - Article
C2 - 30016111
AN - SCOPUS:85050334195
SN - 0893-228X
VL - 31
SP - 885
EP - 897
JO - Chemical research in toxicology
JF - Chemical research in toxicology
IS - 9
ER -