Ochratoxin A-induced mutagenesis in mammalian cells is consistent with the production of oxidative stress.
Ochratoxin A (OTA) is a widespread mycotoxin in food and a powerful nephrocarcinogen in rats. The mutagenicity of OTA has been extensively investigated but with conflicting results, thus leaving open the mechanistic question for OTA carcinogenicity. Here, we examined the mutagenicity of OTA by using well-standardized mutation assays such as the hypoxanthine-guanine phosphoribosyltransferase (HPRT) assay in Chinese hamster V79 cells and the thymidine kinase assay in mouse lymphoma LY5178 cells. OTA-induced HPRT mutations were characterized at the molecular level. In V79 cells, OTA produced a dose- and time-related decrease in cell number as a consequence of the transitory cytostatic effect mediated by G2/M cell cycle arrest. In both mutation assays, OTA was weakly mutagenic and this effect was independent of biotransformation. OTA-induced mutations were characterized by point mutations (48%) and a lack of a detectable reverse-transcription polymerase chain reaction product (52%). The pattern of OTA-induced point mutations was similar to that of spontaneous mutants, suggesting that OTA induced an increase of the endogenous oxidative metabolism but not covalent DNA adducts. Our data support a model where OTA is mutagenic via oxidative DNA damage induction.
Palma
Nieves
N
Department of Environment and Primary Prevention, Istituto Superiore di Sanita', Viale Regina Elena 299, 00161 Rome, Italy.
Cinelli
Serena
S
Sapora
Orazio
O
Wilson
Samuel H
SH
Dogliotti
Eugenia
E
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002458:Cell Fractionation / Q000379:methods; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007940:Leukemia L5178 / Q000235:genetics / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests / Q000379:methods; D009154:Mutation / Q000187:drug effects; D009793:Ochratoxins / Q000633:toxicity*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics
D002273:Carcinogens; D009793:Ochratoxins; C025589:ochratoxin A; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase