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ToxSci Advance Access published online on November 6, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl155
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 11, 2006
Accepted October 25, 2006

Genetic Toxicology

Cytogenetic Damage Induced by Acrylamide and Glycidamide in Mammalian Cells: Correlation with Specific Glycidamide-DNA Adducts

Célia Martins 1 *, Nuno G. Oliveira 2 *, Marta Pingarilho 1, Gonçalo Gamboa da Costa 3, Vanda Martins 1, M. Matilde Marques 4, Frederick A. Beland 5, Mona I. Churchwell 5, Daniel R. Doerge 5, José Rueff 1, and Jorge Francisco Gaspar 1 *

1 Dep. Genetics, Faculty of Medical Sciences, New University of Lisbon (CIGMH), Rua da Junqueira 96, 1349-008 Lisboa, Portugal
2 Dep. Genetics, Faculty of Medical Sciences, New University of Lisbon (CIGMH), Rua da Junqueira 96, 1349-008 Lisboa, Portugal; Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1649-019 Lisboa, Portugal
3 Section of Molecular Carcinogenesis, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
4 Centro de Química Estrutural, Instituto Superior Técnico, 1049-001 Lisboa, Portugal
5 Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR72079, USA

* To whom correspondence should be addressed.
Jorge Francisco Gaspar, E-mail: jgaspar.gene{at}fcm.unl.pt


  Abstract

Acrylamide (AA) is a suspected human carcinogen generated in carbohydrate-rich foodstuffs upon heating. Glycidamide (GA), formed via epoxidation, presumably mediated by cytochrome P450 2E1, is thought to be the active metabolite playing a central role in AA genotoxicity. In this work we investigated DNA damage induced by AA and GA in mammalian cells, using V79 Chinese hamster cells. For this purpose, we evaluated two cytogenetic end-points, chromosomal aberrations (CAs) and sister-chromatid exchanges (SCEs), as well as the levels of specific glycidamide-DNA adducts, namely N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua) and N3-(2-carbamoyl-2-hydroxyethyl)adenine (N3-GA-Ade) using HPLC coupled with tandem mass spectrometry. GA was more cytotoxic and clastogenic than AA. Both AA and GA induced chromosomal aberrations (breaks and gaps) and decreased the mitotic index. GA induced SCEs in a dose-responsive manner; with AA, SCEs were increased at only the highest dose tested (2 mM). A linear dose-response relationship was observed between the GA concentration and the levels of N7-GA-Gua. This adduct was detected for concentrations as low as 1 µM GA. N3-GA-Ade was also detected, but only at very high GA concentrations (≥ 250 µM). There was a very strong correlation between the levels of N7-Gua-GA in the GA- and AA-treated cells and the extent of SCE induction. Such correlation was not apparent for chromosomal aberrations. These data suggest that the induction of SCEs by AA is associated with the metabolism of AA to GA and subsequent formation of depurinating DNA adducts; however, other mechanisms must be involved in the induction of chromosomal aberrations.

Keywords: Acrylamide; Glycidamide; DNA Adducts; Chromosomal Aberrations; Sister Chromatid Exchanges.

* Both authors contributed equally to this work.


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