Ochratoxins: Molecular strategies for developing an antidote

Ochratoxin A (OcA) is a prominent member of a group of mycotoxins which dis play nephrotoxic, genotoxic, teratogenic, carcinogenic and immunosuppressiv e effects and which have also been linked to Balkan Endemic Nephropathy. Th e toxicity of OcA is thought to be primarily due to its inhibition of pheny lalanine-t-RNA synthetase, a phenylalanine-metabolizing enzyme. Based on the three-dimensional structure of phenylalanine-t-RNA synthetase, we have analyzed its interactions with OcA by means of molecular-dynamical simulations and identified three quite different binding modes, all of whi ch suggest an affinity only in the millimolar range. This would seem to be in conflict with toxicological findings frequently cited in textbooks but i s in agreement with recent in vitro studies on purified phenylalanine-t-RNA synthetase, which als exclude this enzyme as the main target for OcA actio n. In vivo, OcA binds preferentially to serum albumin, a plasma protein, with a corresponding effect on its toxicokinetics (retention). Antagonizing this effect would lead to an enhanced elimination rate, thereby reducing all ad verse effects of OcA, as has been demonstrated using albumin-deficient mice . Based on the three-dimensional structure of serum albumin, we have simula ted its interaction with OcA. The long-term goal is the animal-free identif ication of a synthetic antagonist with an affinity between that of the endo genous ligands (e.g. bilirubin) and OcA. Such a substance could - by reduci ng the retention time of the toxin in the body - potentially eliminate all toxic effects of OcA.