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: Synthesis, Structural Identification, and Detection in Human Cells

Arnold S. Groehler, Dominic Najjar, Suresh S. Pujari, Dewakar Sangaraju, Natalia Y. Tretyakova

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)885-897
Number of pages13
JournalChemical research in toxicology
Volume31
Issue number9
DOIs
StatePublished - Sep 17 2018

Bibliographical note

Funding Information:
*E-mail: trety001@umn.edu. Tel: (612) 626-3432. Fax: (612) 624-3869. ORCID Suresh S. Pujari: 0000-0002-0246-3362 Natalia Y. Tretyakova: 0000-0002-0621-6860 Funding This work was supported by the U.S. National Cancer Institute (grant number R01 ES-100670). Notes The authors declare no competing financial interest.

Publisher Copyright:
© 2018 American Chemical Society.

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