Genotoxicity of ochratoxin A and structurally related compounds in Escherichia coli strains: studies on their mode of action.
Ochratoxin A, ochratoxin alpha (its major metabolite in rodents) and seven structurally related substances were assayed for SOS DNA repair inducing activity in Escherichia coli PQ37 strain. At a concentration range of 0.1-4 mM, ochratoxin A, chloroxine, 5-chloro-8-quinolinol, 4-chloro-meta-cresol and chloroxylenol were found to induce SOS-DNA repair in the absence of an exogenous metabolic activation system. Ochratoxin B, ochratoxin alpha, 5-chlorosalicylic acid and citrinin were inactive, but all except ochratoxin alpha were cytotoxic. Thus, the presence of a chlorine at C-5 in ochratoxin A and in other analogues appears to be one determinant of their genotoxicity. In order to ascertain whether this reactivity involves a bacterial glutathione conjugation reaction, we investigated the modifying effect on the genotoxicity of ochratoxin A of amino oxyacetic acid, an inhibitor of cysteine conjugate beta-lyase. Amino oxyacetic acid decreased the cytotoxicity of ochratoxin A but did not alter its genotoxic activity, suggesting the formation of a cytotoxic thiol-containing derivative. The way in which ochratoxin A and some of its active analogues induce SOS DNA repair activity was further investigated in E. coli PQ37 and in three derived strains (PQ300, OG100 and OG400, containing deletions within the oxy R regulon). The response in PQ37 strain was measured in the absence and presence of Trolox C, a hydrosoluble form of vitamin E. Trolox C completely quenched the genotoxicity of ochratoxin A, which was no greater in mutated than in wild type strains. These results implicate an ochratoxin A-derived free radical rather than reduced oxygen species as genotoxic intermediate(s) in bacteria.
Malaveille
C
C
International Agency for Research on Cancer, Lyon, France.
Brun
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G
Bartsch
H
H
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D002739:Chloroquinolinols / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D002953:Citrinin / Q000494:pharmacology; D003408:Cresols / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects*; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D009152:Mutagenicity Tests; D009793:Ochratoxins / Q000737:chemistry / Q000494:pharmacology*; D013014:SOS Response, Genetics / Q000187:drug effects*; D012459:Salicylates / Q000494:pharmacology; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D014992:Xylenes / Q000494:pharmacology
D002739:Chloroquinolinols; D002839:Chromans; D003408:Cresols; D005609:Free Radicals; D009793:Ochratoxins; D012459:Salicylates; D014992:Xylenes; C007027:chloroxylenol; D000625:Aminooxyacetic Acid; C025589:ochratoxin A; C019292:4-chloro-2-cresol; C004357:chloroxine; D002953:Citrinin; D005978:Glutathione; C015751:5-chlorosalicylic acid; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D004121:Dimethyl Sulfoxide