How aspartame prevents the toxicity of ochratoxin A.

Abstract

The ubiquitous mycotoxin ochratoxin A (OTA) is found as a frequent contaminant of a large variety of food and feed and beverage such as beer, coffee and win. It is produced as a secondary metabolite of moulds from Aspergillus and Penicillium genera. Ochratoxin A has been shown experimentally to inhibit protein synthesis by competition with phenylalanine its structural analogue and also to enhance oxygen reactive radicals production. The combination of these basic mechanisms with the unusual long plasma half-life time (35 days in non-human primates and in humans), the metabolisation of OTA into still active derivatives and glutathione conjugate both potentially reactive with cellular macromolecules including DNA could explain the multiple toxic effects, cytotoxicity, teratogenicity, genotoxicity, mutagenicity and carcinogenicity. A relation was first recognised between exposure to OTA in the Balkan geographical area and Balkan Endemic Nephropathy (BEN) with a high incidence (nearly 50 times higher than normal) of urinary tract tumours. Exposure rates of OTA are measurable in blood of humans and animals and are established in several countries including Scandinavia, Germany, France, Italy, Canada, Japan and Northern Africa mainly Tunisia and Egypt. The impact of OTA exposure in non- endemic areas in the world is not known, the rates of exposure being not correlated with the disease records, especially in developed countries, due to lake of well- designed epidemiological studies, genetic polymorphism and maybe to dietary contents of radical scavengers and antioxidants. However the incidence and mortality rates of renal cancer are increasing in European countries and Northern Africa which could be a global resultant of human exposure to natural compounds in food such as mycotoxins and especially ochratoxin A. In addition to special care to prevent the growth of moulds and detoxification measures there was a need for the prevention of the OTA-induced toxic effects once the toxin is ingested. For this purpose several compound have been studied including some therapeutic agents such as piroxicam which cannot be proposed for a large scale use in humans for preventive purpose. Among other compounds, Aspartame, already used as sweetener has shown a real effectiveness in vivo confirmed largely in vitro. When rats exposed to OTA (289 micrograms/kg) by oral route every two days are given 25 mg/kg similarly for several weeks, all the toxic effects including genotoxicity are very efficiently prevented as shown for example by the disappearance of DNA- adducts in tissues excised from treated animals. Aspartame is also effective in washing out the toxin when given afterwards to animals intoxicated by the same oTA doses for several weeks. In vitro, provided that it is added in cell culture medium before OTA it prevent significantly the inhibition of protein synthesis and lipid peroxidation induced by the toxin. Obviously the molecular mechanism mediating the preventive effect of Aspartame is the delivery of phenylalanine by cleavage of the peptide but also the direct effect of the peptide on the bending capacity and transport of the toxin in vivo and in vitro. As a matter of fact when Aspartame is given to animals or added in culture medium the amount of peptide found unchanged (10-15%) may account for a preventive effect as entire peptide.