Protection by desferrioxamine and other hydroxamic acids against tetrachlorohydroquinone-induced cyto- and genotoxicity in human fibroblasts.
Tetrachlorohydroquinone (TCHQ) has been identified as a major toxic metabolite of the widely used wood preservative pentachlorophenol and has also been implicated in its genotoxicity. We have recently demonstrated that protection by the trihydroxamate iron chelator desferrioxamine (DFO) on TCHQ-induced single-strand breaks in isolated DNA was not the result of its chelation of iron but rather of its efficient scavenging of the reactive tetrachlorosemiquinone (TCSQ) radical. In this study, we extended our research from isolated DNA to human fibroblasts. We found that DFO provided marked protection against both the cyto- and genotoxicity induced by TCHQ in human fibroblasts when it was incubated simultaneously with TCHQ. Pretreatment of the cells with DFO followed by washing also provided marked protection, although less efficiently compared with the simultaneous treatment. Similar patterns of protection were also observed for three other hydroxamic acids (HAs): aceto-, benzo-, and salicylhydroxamic acid. Dimethyl sulfoxide, an efficient hydroxyl radical scavenger, provided only partial protection even at high concentrations. In vitro studies showed that the HAs tested effectively scavenged the reactive TCSQ radical and enhanced the formation of the less reactive and less toxic 2,5-dichloro-3, 6-dihydroxy-1,4-benzoquinone (chloranilic acid). The results of this study demonstrated that the protection provided by DFO and other HAs against TCHQ-induced cyto- and genotoxicity in human fibroblasts is mainly through scavenging of the observed reactive TCSQ radical and not through prevention of the Fenton reaction by the binding of iron in a redox-inactive form.
Witte
I
I
Carl von Ossietzky Universitaet Oldenburg, FB 7 and ICBM, Oldenburg, Germany.
Zhu
B Z
BZ
Lueken
A
A
Magnani
D
D
Stossberg
H
H
Chevion
M
M
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D003676:Deferoxamine / Q000494:pharmacology*; D005347:Fibroblasts; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009153:Mutagens / Q000633:toxicity; D010084:Oxidation-Reduction; D010416:Pentachlorophenol / Q000378:metabolism / Q000633:toxicity
D016166:Free Radical Scavengers; D005609:Free Radicals; D006873:Hydroquinones; D006877:Hydroxamic Acids; D009153:Mutagens; C044578:2,3,5,6-tetrachlorohydroquinone; D010416:Pentachlorophenol; D003676:Deferoxamine