ASPARTAME AS A PREVENTIVE AGENT OF CHRONIC TOXIC EFFECTS OF OCHRATOXIN A IN EXPERIMENTAL-ANIMALS

Ochratoxin A (OTA) is a mycotoxin produced by ubiquitous Aspergilli, m ainly by Aspergillus ochraceus and also by Penicillium verrucosum. It is found all over the world in feed and Human food and blood as well a s in animal blood and tissues. The most threatening effects of OTA are nephrotoxicity and carcinogenicity, since this mycotoxin is nephrotox ic to all animal species studied so far and is increasingly involved i n the Balkan Endemic Nephropathy (BEN) a human chronic interstitial ne phropathy which is most of the time associated to urinary tract tumour s. Many data are available on the different mechanisms whereby OTA is absorbed, transported, distributed, metabolised, accumulated and/or el iminated in vivo. Its molecular mode of action in vivo and in vitro in the inhibition of total protein synthesis and of a specific protein s uch as renal phosphoenolpyruvate carboxykinase (PEPCK) are also well d ocumented. There are evidence of the implication of oxidative pathways in the OTA-induced cellular damage and in its genetoxicity, the mecha nism of which is being more and more understood. Since it seems imposs ible to avoid foodstuffs contamination by toxigenic fungi, detoxificat ion and detoxication for OTA were needed. The results of these investi gations showed that some of these potential antidotes were efficient i n preventing the main OTA toxic effects whereas some others were not. Promising compounds are structural analogues, and/or compounds having a high binding affinity for plasma proteins such as A19 (Aspartame), p iroxicam, a NSAID, some enzymes such as SOD and catalase, radical scav engers, vitamins, PG-synthesis inhibitors, (such as piroxicam), pH mod ificators such as sodium bicarbonate, adsorbent resin such as cholesty ramine etc. Some of the results obtained in vivo needed to be confirme d in vitro in order to know how to use safely these antidotes. The mos t globally acting compound seemed to be Aspartame, a structural analog ue of OTA and phenylalanine. When given to rats (25mg/kg/48h) combined to OTA (289 mu g/kg/48h) for several weeks, it largely prevented OTA- nephrotoxicity and genotoxicity. When given after intoxication of anim als with OTA it washed out the toxin efficiently. In vitro, A19 (10 mu g/ml) prevented OTA (20 to 500 mu g/ml) binding to plasma proteins. I t also prevented its cytotoxicity in a renal cell-line in culture. Sin ce Aspartame is not toxic and of a very convenient use, it is proposed for the prevention of the ochratoxin A-induced toxic effects.