Alpha,beta-unsaturated carbonyl compounds: induction of oxidative DNA damage in mammalian cells.
Alpha,beta-unsaturated carbonyl compounds occur in food and other environmental media. Due to their reactivity with cellular nucleophiles (e.g. Michael adduct formation with DNA bases and with glutathione) they might represent a potential health risk. In this study, induction of oxidative DNA damage was investigated in mammalian cells, as a consequence of glutathione depletion induced by selected food relevant 2-alkenals, including E-(2)-hexenal (HEX), (2E,4E)-2,4-hexadienal (HEXDI) and (E)-2-cinnamaldehyde (CA) and the cyclic analogue 2-cyclohexen-1-one (CHX). Oxidative DNA breakage was monitored with the Comet assay, using treatment with formamidopyrimidine-DNA glycosylase (FPG). Total cellular glutathione (tGSH) was determined in a kinetic, photometric assay. After 1 h incubation of V79 cells with HEX (100 microM) and CHX (300 microM), HEXDI and CA (300 microM each), tGSH was depleted down to <20% of control (viability >85%). Under these conditions, FPG-sensitive sites were not observed; moderate direct DNA breakage, however, was detectable. During 3 h post-incubation (without test compound) distinct oxidative DNA breakage occurred in HEX- and CA-, but not in CHX- and HEXDI-pretreated cells. Direct DNA breakage was markedly diminished, most probably by repair processes, and tGSH concentrations were observed to increase again within 3 h post-treatment. The results give strong evidence for alkenal-mediated oxidative stress contributing to cytotoxic/genotoxic cell damage. The extent of oxidative stress appears to be influenced by structure-specific properties of the alkenals.
Janzowski
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Department of Chemistry, Division of Food Chemistry and Environmental Toxicology, University of Kaiserlautern, 67663 Kaiserslautern, Germany. janzo@rhrk.uni-kl.de
Glaab
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Mueller
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Straesser
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U
Kamp
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HG
Eisenbrand
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D000171:Acrolein / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D000447:Aldehydes / Q000737:chemistry / Q000633:toxicity*; D000466:Alkadienes / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003512:Cyclohexanones / Q000737:chemistry / Q000633:toxicity; D004249:DNA Damage; D043382:DNA-Formamidopyrimidine Glycosylase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008322:Mammals; D018384:Oxidative Stress / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors
D000447:Aldehydes; D000466:Alkadienes; D003512:Cyclohexanones; C028215:2-cyclohexen-1-one; C051750:2-hexenal; D000171:Acrolein; C079389:2,4-hexadienal; D043382:DNA-Formamidopyrimidine Glycosylase; D005978:Glutathione; C012843:cinnamaldehyde