Glutathione S-transferase polymorphisms and ochratoxin A toxicity in primary human urothelial cells

The mycotoxin ochratoxin A (OTA) is a worldwide contaminant of human food. OTA is genotoxic. immunotoxic. teratogenic and carcinogenic in rodents and can cause nephropathy in pigs. High amounts of OTA call cause nephropathy in humans. Moreover. evidence has been accumulated that OTA is a genotoxic carcinogen. Nevertheless. the mechanism that leads to OTA toxicity has not been fully resolved and it is discussed if a bioactivation of OTA is necessary or not. In this study the genotoxicity of OTA was investigated in primary human urothelial cells by means of alkaline single cell gel electrophoresis (Comet assay). Primary cultured human urothelial cells derived from tissue specimens of urological patients were incubated with 100 mu M OTA for 3 h. In contrast to recently published results in MDCK cell lines. the cell cultures showed great interindividual differences ill the extent of DNA damage. To evaluate these great interindividual differences the influence of the genotype of the isoenzymes of glutathione S-transferase (GST), namely GSTT1, GSTM1 and GSTP1 oil the gonotoxic potential of OTA was examined. The genotypes of these polymorphic enzymes were determined by polymerase chain reaction (PCR) and the distributions of the genotypes were correlated with the extent of DNA damage. We found associations between the genotypes of the polymorphic GST isoenzymes and the extent of DNA damage between subgoups with and without OTA-related DNA damage. From these results we conclude that genetic predisposition has the potential to influence OTA genotoxicity. (c) 2006 Elsevier Ireland Ltd. All rights reserved.