title: Aldehydes with high and low toxicities inactivate cells by damaging distinct cellular targets.
abstract: Aldehydes are genotoxic and cytotoxic molecules and have received considerable attention for their associations with the pathogenesis of various human diseases. In addition, exposure to anthropogenic aldehydes increases human health risks. The general mechanism of aldehyde toxicity involves adduct formation with biomolecules such as DNA and proteins. Although the genotoxic effects of aldehydes such as mutations and chromosomal aberrations are directly related to DNA damage, the role of DNA damage in the cytotoxic effects of aldehydes is poorly understood because concurrent protein damage by aldehydes has similar effects. In this study, we have analysed how saturated and α,β-unsaturated aldehydes exert cytotoxic effects through DNA and protein damage. Interestingly, DNA repair is essential for alleviating the cytotoxic effect of weakly toxic aldehydes such as saturated aldehydes but not highly toxic aldehydes such as long α,β-unsaturated aldehydes. Thus, highly toxic aldehydes inactivate cells exclusively by protein damage. Our data suggest that DNA interstrand crosslinks, but not DNA-protein crosslinks and DNA double-strand breaks, are the critical cytotoxic DNA damage induced by aldehydes. Further, we show that the depletion of intracellular glutathione and the oxidation of thioredoxin 1 partially account for the DNA damage-independent cytotoxicity of aldehydes. On the basis of these findings, we have proposed a mechanistic model of aldehyde cytotoxicity mediated by DNA and protein damage.
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
authors.forename: Ming-Zhang
authors.initials: MZ
authors.lastname: Xie
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan; Department of Zoology, Biological Science Building, Faculty of Science, Minia University, Minia 61519, Egypt.
authors.forename: Mahmoud I
authors.initials: MI
authors.lastname: Shoulkamy
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan; Department of Pathology, Medical Research Division, National Research Centre, El-Bohouth St., Dokki, Giza 12311, Egypt.
authors.forename: Amir M H
authors.initials: AM
authors.lastname: Salem
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Oba
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Goda
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan. Electronic address: ideh@hiroshima-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ide
mesh_terms: D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D003412:Cricetulus; D004249:DNA Damage; D053938:DNA Fragmentation; D004260:DNA Repair; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000447:Aldehydes; D013879:Thioredoxins; D005978:Glutathione
keywords: Aldehyde; Cytotoxicity; DNA damage; DNA repair; Protein damage