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Mechanism of action of ochratoxin A. Paper-63988. Finally, the recent results of Pfohl-Leszkowicz et al.
It is also immunosuppressive, teratogenic and carcinogenic.
We showed recently that it inhibits phenylalanine hydroxylase. Paper-63988.
The biochemical and molecular aspects of its action were first studied in bacteria.
Ochratoxin A might act on other enzymes that use phenylalanine as a substrate. Paper-63988.
The inhibition is competitive to phenylalanine and is reversed by an excess of this amino acid. Paper-63988.
Ochratoxin A has a number of toxic effects in mammals, the most notable of which is nephrotoxicity. Paper-63988.
Recently, ochratoxin A was also found to enhance lipid peroxidation both in vitro and in vivo. Paper-63988.
An excess of phenylalanine also prevents inhibition of protein synthesis in cell cultures and in vivo. Paper-63988.
This suggestion was confirmed by the demonstration that ochratoxin A inhibits bacterial, yeast and liver phenylalanyl-tRNA synthetases. Paper-63988.
The appearance of 'magic spots' (ppGpp and pppGpp) pointed to inhibition of the charging of transfer ribonucleic acids (tRNA) with amino acids. Paper-63988.
The effect of ochratoxin A on protein synthesis is followed by an inhibition of RNA synthesis, which might affect proteins with a high turnover. Paper-63988.
In addition, the phenylalanine moiety of ochratoxin A is partially hydroxylated to tyrosine by incubation with hepatocytes and in vivo. Paper-63988.
This inhibition might have an important effect on cell or mitochondrial membranes and be responsible for the effects on mitochondria that have been shown by several authors.
Analogues of ochratoxin A in which phenylalanine has been replaced by other amino acids have similar inhibitory effects on the respective amino acid-specific aminoacyl tRNA synthetases. Paper-63988.
This competitive action with phenylalanine might explain why this amino acid prevents the immuno-suppressive effect of ochratoxin A and partially prevents its teratogenic and nephrotoxic actions. Paper-63988.
(this volume), who showed the formation of DNA adducts mainly in kidney but also in liver and spleen, explain the DNA single-strand breaks observed previously in mice and rats after acute and chronic treatment.
4R-Hydroxyochratoxin A, a metabolite of ochratoxin A, has a similar action, whereas ochratoxin alpha (the dihydroisocoumarin moiety) and ochratoxin B ( ochratoxin A without chlorine) have no effect. Paper-63988.
Ochratoxin A also lowers the level of phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis; this inhibition is reported to be due to a specific degradation of mRNA that codes for this enzyme. Paper-63988.
As a consequence, protein synthesis is inhibited, as shown with hepatoma cells in culture, with Madin Darby canine kidney cells (which are much more sensitive) and in vivo in mouse liver, kidney and spleen, the inhibition being more effective in the latter two organs.
Important links !
iHOP - Information Hyperlinked over Proteins .
Concept & Implementation by Robert Hoffmann.