Inhibition of Na+, K+-ATPase activity in rat striatum by the metabolites accumulated in Lesch-Nyhan disease

In the present study, we investigated the in vitro effect of hypoxanthine, xanthine and uric acid, metabolites accumulating in tissue of patients with Lesch-Nyhan disease, on Na+, K+-ATPase activity in striatum of neonate rats. Results showed that all compounds significantly inhibited Na+, K+-ATPase activity. We also studied the kinetics of the inhibition of Na+, K+-ATPase activity caused by hypoxanthine. The apparent K-m and V-max of Na+, K+-ATPase activity for ATP as the substrate and hypoxanthine as the inhibitor were 0.97 mM and 0.69 nmol inorganic phosphate (Pi) released per min per mg of protein, respectively. K-i-value was 1.9 muM, and the inhibition was of the non-competitive type. We also observed that the inhibitory effects of hypoxanthine, xanthine and uric acid probably occur through the same mechanism, suggesting a common binding site for these oxypurines on Na+, K+-ATPase. Therefore, it is conceivable that inhibition of brain Na+, K+-ATPase activity may be involved at least in part in the neuronal dysfunction characteristic of patients with Lesch-Nyhan disease. (C) 2003 ISDN. Published by Elsevier Ltd. All rights reserved.