Aspartame as a Preventive Agent of Chronic Toxic Effects of Ochratoxin a in Experimental Animals

Abstract

Ochratoxin A (OTA) is a mycotoxin produced by ubiquitous Aspergilli, mainly by Aspergillus ochraceus and also by Penicillium verrucosum. It is found all over the world in feed and Human food and blood as well as in animal blood and tissues.

The most threatening effects of OTA are nephrotoxicity and carcinogenicity, since this mycotoxin is nephrotoxic to all animal species studied so far and is increasingly involved in the Balkan Endemic Nephropathy (BEN) a human chronic interstitial nephropathy which is most of the time associated to urinary tract tumours.

Many data are available on the different mechanisms whereby OTA is absorbed, transported, distributed, metabolised, accumulated and/or eliminated in vivo. Its molecular mode of action in vivo and in vitro in the inhibition of total protein synthesis and of a specific protein such as renal phosphoenolpyruvate carboxykinase (PEPCK) are also well documented.

There are evidence of the implication of oxidative pathways in the OTA-induced cellular damage and in its genetoxicity, the mechanism of which is being more and more understood.

Since it seems impossible to avoid foodstuffs contamination by toxigenic fungi, detoxification and detoxication for OTA were needed.

The results of these investigations showed that some of these potential antidotes were efficient in 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), piroxicam, a NSAID, some enzymes such as SOD and catalase, radical scavengers, vitamins, PG-synthesis inhibitors, (such as piroxicam), pH modificators such as sodium bicarbonate, adsorbent resin such as cholestyramine etc. Some of the results obtained in vivo needed to be confirmed in vitro in order to know how to use safely these antidotes. The most globally acting compound seemed to be Aspartame, a structural analogue of OTA and phenylalanine. When given to rats (25mg/kg/48h) combined to OTA (289μg/kg/48h) for several weeks, it largely prevented OTA-nephrotoxicity and genotoxicity. When given after intoxication of animals with OTA it washed out the toxin efficiently.

In vitro, A19 (10μg/ml) prevented OTA (20 to 500 μg/ml) binding to plasma proteins.

It also prevented its cytotoxicity in a renal cell-line in culture. Since Aspartame is not toxic and of a very convenient use, it is proposed for the prevention of the ochratoxin A-induced toxic effects.