Mutagenicity and genotoxicity of the mycotoxin ochratoxin A

Natural occurrence of the mycotoxin ochratoxin A in food commodities has been linked to endemic diseases in certain human populations, where a high incidence of nephropathy is observed (Balkan endemic nephropathy). The increase of renal disease is accompanied with a high risk for urinary tract tumours. Despite epidemiological and experimental evidence for the carcinogenicity of ochratoxin A the underlying mechanism needs to be established. The pivotal role of cytochrome P450 in the mutagenicity of ochratoxin A could be demonstrated in experiments with cell lines stably expressing the human cytochrome P450 enzymes. CYP1A1, 1A2, 2C10 and 3A4, which were able to activate the non-mutagenic ochratoxin A into mutagenic metabolites. In the cell lines the bacterial lacZ' gene was used as reporter gene for mutagenicity. Sequencing of the lacZ' gene resulted in the detection of large deletions. In addition, in metabolically competent rat hepatocytes an increase of single strand breaks could be observed by means of the DNA alkaline elution assay. These DNA alterations could be related to biotransformation processes, indicating extensive metabolism of ochratoxin A. The discrepancies found between microsomal and cellular metabolism leads to the conclusion that ochratoxin A mediated mutagenicity requires additional processing of cytochrome P450 derived metabolism.