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 microM, 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.
Bavaresco
Caren S
CS
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Zugno
Alexandra I
AI
Tagliari
Bárbara
B
Wannmacher
Clóvis M D
CM
Wajner
Moacir
M
Wyse
Angela T S
AT
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D019271:Hypoxanthine / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D007926:Lesch-Nyhan Syndrome / Q000378:metabolism*; D016014:Linear Models; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013570:Synaptic Membranes / Q000187:drug effects*; D014527:Uric Acid / Q000494:pharmacology; D019820:Xanthine / Q000494:pharmacology
D019820:Xanthine; D014527:Uric Acid; D019271:Hypoxanthine; D000254:Sodium-Potassium-Exchanging ATPase