Genotoxicity of glycidamide in comparison to 3-N-nitroso-oxazolidin-2-one.
Acrylamide (AA) is generated by thermal processing of foods, depending on processing conditions and precursor availability. AA is not genotoxic by itself but becomes activated to its genotoxic metabolite glycidamide (GA) via epoxidation, mediated primarily by cytochrome P450 2E1. In the Comet assay in V79 cells and in human lymphocytes, GA induced DNA damage down to 300 microM concentration (4 h). After post-treatment with the DNA repair enzyme formamidopyrimidine-DNA-glycosylase (FPG), DNA damage became already detectable at 10 microM (4 h). By comparison, the N-nitroso compound 3- N-nitroso-oxazolidin-2-one (NOZ-2) is a much stronger genotoxic agent, significantly inducing DNA damage already at 15 min (3 microM). Post-treatment with FPG in this case did not enhance response. GA induced DNA damage in V79 cells rather slowly, with first response detectable at 4 h. The hPRT forward mutation test encompasses 5 days of expression time during which also repair can take place. GA-induced hPRT mutations only became detectable at concentrations of 800 microM and above. This is 80-fold higher than the lowest significant response to GA in the Comet assay (10 microM with FPG). In contrast, NOZ-2 was as effective in the hPRT test as in the Comet assay (3 microM). These results demonstrate substantial differences in the genotoxic potency of GA and NOZ-2. Whereas NOZ-2 is a pontent genotoxic mutagen, GA in comparison shows only low genotoxic and mutagenic potential, presumably as a result, at least in part, of preferential N7-G alkylation.
Baum
Matthias
M
Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schroedinger-Strasse 52, Kaiserslautern 67663, Germany. mbaum@rhrk.uni-kl.de
Loeppky
Richard N
RN
Thielen
Silke
S
Eisenbrand
Gerhard
G
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair; D004852:Epoxy Compounds / Q000633:toxicity*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008168:Lung; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000187:drug effects; D009602:Nitrosamines / Q000633:toxicity*; D023303:Oxazolidinones / Q000633:toxicity*
D004852:Epoxy Compounds; D009153:Mutagens; D009602:Nitrosamines; D023303:Oxazolidinones; C036494:3-nitroso-2-oxazolidone; C071834:glycidamide; D007041:Hypoxanthine Phosphoribosyltransferase