Inhibition of Mitochondrial Carnitine Palmitoyl Transferase A in Vivo with Methyl 2-Tetradecylglycidate (Methyl Palmoxirate) and Its Relationship to Ketonemia and Glycemia 1
Inhibition of Mitochondrial Carnitine Palmitoyl Transferase A in Vivo with Methyl 2-Tetradecylglycidate (Methyl Palmoxirate) and Its Relationship to Ketonemia and Glycemia 1
复制标题
2-十四烷基甘油酸甲酯（棕榈氧酸甲酯）对体内线粒体肉碱棕榈酰转移酶 A 的抑制及其与酮血症和血糖的关系 1
DOI：
10.3181/00379727-178-42012
复制
发表时间：
1985
影响因子：
--
通讯作者：
T. Kiorpes
中科院分区：
文献类型：
--
作者：
G. Tutwiler;H. J. Brentzel;T. Kiorpes
摘要采用口服降糖药2-十四酰甘氨酸甲酯（Me-TDGA）体外抑制线粒体肉碱棕榈酰转移酶A (CPT-A)，研究CPT抑制作用与正常和糖尿病大鼠酮血症和血糖变化的关系。口服Me-TDGA后，离体大鼠肝脏线粒体CPT活性显著降低，只有地黄皂苷释放的CPT- a外酶部分活性降低。线粒体脂肪酰基辅酶a合成酶未受抑制。口服0.1-2.5 mg/kg Me-TDGA可产生剂量依赖性血浆酮降低和肝脏CPT抑制。单次剂量超过2.5 mg/kg时，po、心脏和骨骼肌CPT也持续受到抑制。1 mg/kg po对肝酶的影响持续至少48小时，而对酮类的影响在36小时后消失。Me-TDGA对肝脏CPT的抑制程度不受糖尿病或饮食状况的影响。在低剂量（0.05 ~ 0.25 mg/kg, po）下，最敏感的参数是对肝脏CPT的抑制。血浆酮和CPT的剂量比降血糖所需的剂量少10倍（0.1 mg/kg），从而使Me-TDGA成为已知的最有效的降酮化合物。综上所述，Me-TDGA在CPT-A阶段抑制肝脏β-氧化可以解释该化合物在禁食的正常和糖尿病大鼠中有效的降酮作用。为了抑制肌肉CPT和降低血糖，需要更高的急性剂量。
Abstract The oral hypoglycemic agent, methyl 2-tetradecylglycidate (Me-TDGA), which inhibits in vitro mitochondrial carnitine palmitoyl transferase A (CPT-A) was used to study the relationship of CPT inhibition to changes in ketonemia and glycemia in normal and diabetic rats. After oral administration of Me-TDGA, the CPT activity of isolated rat liver mitochondria was substantially reduced with only the presumed outer enzyme fraction CPT-A released by digitonin treatment showing reduced activity. Mitochondrial fatty acyl-CoA synthetase was not inhibited. Oral doses of 0.1-2.5 mg/kg Me-TDGA produced both a dose-dependent lowering of plasma ketones and an inhibition of liver CPT. With single doses in excess of 2.5 mg/kg, po, heart and skeletal muscle CPT were also consistently inhibited. The effect on the liver enzyme persisted for at least 48 hr following 1 mg/kg, po, while the effect on ketones disappeared by 36 hr. The degree of inhibition of liver CPT produced by Me-TDGA was not altered by diabetes or the dietary state. At low doses (0.05-0.25 mg/kg, po), the most sensitive parameter was inhibition of hepatic CPT. Both plasma ketones and CPT were lowered with doses 10-fold less (0.1 mg/kg) than were required for blood glucose lowering, thus making Me-TDGA the most potent hypoketonemic compound known. In conclusion, inhibition of liver β-oxidation at the stage of CPT-A by Me-TDGA can explain the potent hypoketonemic effects of this compound in fasted normal and diabetic rats. Higher acute doses are needed for both inhibition of muscle CPT and lowering of blood glucose.
影响因子：
4.1
作者：
MCGARRY, JD;MILLS, SE;FOSTER, DW
通讯作者：
FOSTER, DW