[Studies on the mechanism of metabolic acidosis observed in the children treated with anticonvulsants].

Clinical and experimental studies were performed on the mechanisms of metabolic acidosis observed in the children with epilepsy who had long been treated with anticonvulsants such as phenobarbital (PB) or diphenylhydantoin (DPH). The effect of the anticonvulsants was studied on the erythrocyte carbonic anhydrase isozymes (CA-B and CA-C) and on the calcium ion metabolism. The results obtained were as follows: (1) Ten cases with metabolic acidosis were found in 37 cases of epilepsy (27%). Hypocalcemia and high alkaline phosphatase activity in the serum were observed in the acidotic cases. The specific activity of erythrocyte CA-B isozyme was significantly lower in the acidotic cases as compared to those in nonacidotic cases or normal individuals, suggesting that the metabolic acidosis may bring about an inhibition of this enzyme. (2) In vitro experiments were performed to further study the effect of DPH on the erythrocyte CA-B and CA-C. Incubation of the enzymes with DPH resulted in an inhibition of their activities. Affinity binding of DPH to the enzymes was studied using a gel filtration method. The binding of DPH was not replaced by the presence of salicylate, indicating that the binding is non-specific. The addition of ethylenediamine tetraacetic acid did not show any influence on the binding, suggesting that the binding is not chelate-bound with zinc ion which locates at the active center of the enzyme. The binding of DPH was not competitive with respect to acetazolamide which is known to have an affinity for the active center of the enzyme. These results suggest that the binding site of DPH for the enzyme is in the vicinity of its active center, however definitely different from those of acetazolamide. PB was supposed to behave in the same manner as DPH for carbonic anhydrases. (3) This study lead to the conclusion that a long term treatment with PB or DPH specifically inhibits the activity of carbonic anhydrases in erythrocytes. The inhibition of the enzyme activity may result in the metabolic acidosis. Imbalanced calcium ion metabolism was supposed to be induced by the acidosis. The considerable care is requisite for a long-term treatment of anticonvulsants.