Studies on the inhibition of gluconeogenesis by oxalate.
Studies on the inhibition of gluconeogenesis by oxalate.
复制标题
草酸盐抑制糖异生的研究。
DOI：
10.1016/0304-4165(80)90044-6
复制
发表时间：
1980
期刊：
影响因子：
--
通讯作者：
Harris,RA
中科院分区：
文献类型：
--
作者：
Yount,EA;Harris,RA
草酸被证明进入离体大鼠肝细胞，并抑制从乳酸，丙酮酸和丙氨酸，但不从谷氨酰胺，脯氨酸，丙酸或二羟丙酮的代谢。草酸盐显然通过抑制丙酮酸羧化酶发挥作用（EC 6.4.1.1）。已知它抑制分离的酶，并且在缺乏碳酸氢盐的培养基中对丙酮酸羧化酶的抑制作用更大，其中丙酮酸羧化酶活性限制了途径的总速率。观察到天冬酰胺对糖异生有轻微的抑制作用，这表明草酸盐也可能抑制另一个位点的糖异生。细胞外Ca ~（2+）的螯合作用并不抑制细胞的增殖。与草酸盐相比，其他钙离子螯合剂对钙离子的生成影响不大。草酸盐在低钙培养基和含2.6mM钙的培养基中均能有效地抑制胚性愈伤组织的发生。细胞内Ca 2+的螯合作用似乎也不太重要，因为草酸盐不能阻断肾上腺素、血管加压素和血管紧张素的糖原分解作用，这些物质被认为是通过Ca 2+作为第二信使发挥作用的。可以想象，对草酸盐生成的抑制可能有助于草酸盐的毒性作用和二氯乙酸盐（一种代谢为草酸盐的化合物）的降血糖作用。然而，草酸并没有引起低血糖症的乳鼠，模型在体内系统非常依赖于新生维持正常的血糖水平。因此，在草酸盐毒性和二氯醋酸盐的降血糖作用中，抑制血管生成可能不太重要。
Oxalate was shown to enter isolated rat hepatocytes and to inhibit gluconeogenesis from lactate, pyruvate, and alanine, but not from glutamine, proline, propionate or dihydroxyacetone. Oxalate apparently acts by inhibiting pyruvate carboxylase (EC 6.4.1.1). It is known to inhibit the isolated enzyme, and inhibition of gluconeogenesis was much greater in a bicarbonate-deficient medium where pyruvate carboxylase activity limits the overall rate of the pathway. A slight inhibition of gluconeogenesis from asparagine was observed, suggesting that oxalate may also inhibit gluconeogenesis at another site. Chelation of extracellular Ca2+does not contribute to the inhibition of gluconeogenesis. Compared to oxalate, other Ca2+chelators have little effect upon gluconeogenesis. Also, oxalate inhibits gluconeogenesis effectively both in low Ca2+medium and in medium containing 2.6 mM Ca2+. Chelation of intracellular Ca2+also appears to be of little importance, since oxalate does not block the glycogenolytic effects of epinephrine, vasopressin, and angiotensin which are thought to act via Ca2+as the second messenger. The inhibition of gluconeogenesis could conceivably contribute to the toxic actions of oxalate and to the hypoglycemic action of dichloroacetate, a compound that is metabolized to oxalate. However, oxalate did not cause hypoglycemia in the suckling rat, a model in vivo system very dependent upon gluconeogenesis for maintenance of normal blood glucose levels. Thus, inhibition of gluconeogenesis is probably of little importance in oxalate toxicity and the hypoglycemic effects of dichloroacetate.