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

Abstract

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 Km and Vmax of Na+, K+-ATPase activity for ATP as the substrate and hypoxanthine as the inhibitor were 0.97mM and 0.69nmol inorganic phosphate (Pi) released per min per mg of protein, respectively. Ki-value was 1.9μM, 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.