engleski

Ochratoxin A is an effective inhibitor of phenylalanine hydroxylase in vivo

Ochratoxin A (OTA) a mycotoxin produced by storage moulds (Aspergillus and Penicillium spp.) on variety of foodstuff of vegetable or animal origin has been implicated as a causal agent in the aetiology of Balkan endemic nephropathy in humans and in acute ochratoxicosis in agricultural animals. A number of biochemical changes have been described primarily in the proximal kidney tubule and in the liver after natural or experimental exposure to toxin). OTA decreased the rate of protein synthesis and rate of RNA synthesis, most probably by competing with phenylalanine for the Phe-t-RNA synthetase. Inhibition of phenylalanine hydroxylase and other enzymes that use phenylalanine as substrate is based on the structural homology of OTA with that aminoacid. Its chemical structure involves 5'chlorinated-3, 4- dihidro-3-methylisocumarin moiety (OTA-alpha) linked to 1-phenylalanine. We have examined the effects of low doses of OTA on the activity of phenylalanine hydroxylase in kidney and liver of experimental animals. Daily administration of OTA in doses of 50 mg/kg b.w. caused a significant drop in the liver enzyme activity after 10 and after 35 days of treatment, respectively. The same concentration of OTA has not provoked statistically significant changes in enzyme activity in the kidney (Table 1). We examined the kinetic parameters of the inhibition and found the Ki (OTA)= 0.019 + 0.002 mM for liver and Ki (OTA)= 0.12 + 0.026 mM for kidney enzyme, respectively. However, since the concentration of phenylalanine in kidney is significantly higher than in liver, the effect of competitive inhibition is more pronounced in liver tissue. Although OTA was found to be a competitive inhibitor of hydroxylase in vitro, the changes in the body appear to be more complex, involving disturbance in the regulation of the whole system for phenylalanine hydroxylation. Toxicity of OTA could be reduced by simultaneous application of OTA (50 mg/kg b.w./daily) and phenylalanine (500 mg/b.w./ daily) treatment. Inhibition of phenylalanine hydroxylase was reduced for about 12 % after 10 days of combined treatment and activity was almost completely preserved after 35 days of experiment.(Table 1) The results obtained suggest that daily administration of OTA in low doses for 35 days produced strong hepatotoxic effects which could be reduced through competitive action of L-phenylalanine.

ochratoxin A; phenylalanine hydroxylase

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