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Determination of structure of ochratoxin A metabolites and DNA adducts in various tissues in relation to its biotransformation

OTA was incubated with different enzymes in the presence of DNA-oligomers and assessed DNA modifications. OTA induces breaks in the oligomers. DNA modifications on adenine and guanine were induced by OTA in polymeric nucleosides in presence of pig kidney microsomes. Cross-links were also formed in poly dG-dC. Pig liver and kidney microsomes formed several OTA-metabolites.

Two guanine OTA-DNA adducts (O-C8-dG-OTA & C-C8-dG-OTA) have been synthesized by Pr Manderville (Guelp, CA). In postlabelling analysis, both adducts comigrate with OTA-DNA adducts formed in kidney of rats developing tumours.C-C8-dG-OTA is also formed in kidney of pig fed OTA.

The data show that OTA and one of its metabolite is covalently bound on guanine. Some metabolites extracted from cells treated with OTA and from tissues of pigs were characterized by mass spectrometry, notably OP-OA, 4R-OH-OA, 10-OH-OA, OTB and a dechlorinated OTA-derivative different from OTB. Metabolites formation is correlated with DNA adduct formation. Altogether, it has been demonstrated that OTA is a direct genotoxin after metabolic activation.

In addition, the mechanism of cell death induced by OTA was analysed. OTA in epithelial bronchial cells induced necrosis, although at the beginning of the incubation and for low dose an increase of condensate chromatin was observed. The enzymes responsible of apoptosis were not induced.

In pigs, OTA-modulation of the expression of COX1, COX2 and 5-LIPOX is different in genders. COX1 was inhibited in male cortex, an over-expression is observed in females. Thus OTA decreases protection of kidney function due to COX1, and increases risk of cancer link to over-expression of COX2 in male.

The main DNA adduct observed in human kidney tumour of patients exposed to OTA as demonstrated by OTA in blood and kidney tissues of these patients, in rat treated by OTA and in pig fed OTA are formed when enzymes are expressed. DNA-binding of OTA is related to the formation of some metabolites, some of them being already identified by mass spectrometry.

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Institut National Polytechnique de Toulouse
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