RESUMO
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 N6-(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.
Assuntos
Carcinógenos/química , Adutos de DNA/química , Compostos de Epóxi/química , Pirimidinas/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Carcinógenos/toxicidade , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , DNA/efeitos dos fármacos , DNA/metabolismo , Adutos de DNA/análise , DNA Glicosilases/genética , Relação Dose-Resposta a Droga , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/toxicidade , Técnicas de Diluição do Indicador , Camundongos , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrofotometria Ultravioleta/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
Appendicitis is one of the most common surgical emergencies, and surgical intervention remains the gold standard for curative treatment. Although laparoscopic appendectomy is associated with less pain, shorter hospital stays, and earlier mobilization, it is also more frequently complicated by postoperative abscesses. Retained appendicoliths are a rare complication that can serve as a nidus for repeated infections. Laparoscopic removal of the stone can provide definitive source control and reduce repeated hospital admissions. There are many surgical approaches for retrieval and this case, in particular, describes a laparoscopic hand-assisted approach while simultaneously using an interventional radiologic drain to assist with localization.