莱施-奈恩病中积累的代谢产物对大鼠纹状体中钠钾ATP酶活性的抑制作用。

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

作者信息

Bavaresco Caren S, Zugno Alexandra I, Tagliari Bárbara, Wannmacher Clóvis M D, Wajner Moacir, Wyse Angela T S

机构信息

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.

出版信息

Int J Dev Neurosci. 2004 Feb;22(1):11-7. doi: 10.1016/j.ijdevneu.2003.11.002.

DOI:10.1016/j.ijdevneu.2003.11.002

PMID:15013074

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 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.

摘要

在本研究中，我们调查了次黄嘌呤、黄嘌呤和尿酸（莱施-奈恩病患者组织中积累的代谢产物）对新生大鼠纹状体中Na(+)、K(+)-ATP酶活性的体外作用。结果显示，所有化合物均显著抑制Na(+)、K(+)-ATP酶活性。我们还研究了次黄嘌呤对Na(+)、K(+)-ATP酶活性抑制的动力学。以ATP为底物、次黄嘌呤为抑制剂时，Na(+)、K(+)-ATP酶活性的表观K(m)和V(max)分别为0.97 mM和每分钟每毫克蛋白质释放0.69 nmol无机磷酸（Pi）。抑制常数（K(i)）值为1.9 microM，抑制作用为非竞争性类型。我们还观察到，次黄嘌呤、黄嘌呤和尿酸的抑制作用可能通过相同机制发生，这表明这些氧嘌呤在Na(+)、K(+)-ATP酶上有一个共同的结合位点。因此，可以想象，脑Na(+)、K(+)-ATP酶活性的抑制可能至少部分参与了莱施-奈恩病患者的神经元功能障碍。