Koundakjian P P, Turnbull D M, Bone A J, Rogers M P, Younan S I, Sherratt H S
Biochem Pharmacol. 1984 Feb 1;33(3):465-73. doi: 10.1016/0006-2952(84)90242-9.
Ethyl 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA) is strongly hypoglycaemic in fasted normal and diabetic rats [H. P. O. Wolf, K. Eistetter and G. Ludwig, Diabetologia 22, 456 (1982)]. POCA was fed for 12 weeks to rats on a standard low-fat (3%) diet at levels of 0.05% and 0.2% to give daily intakes of about 50 and 200 mg/per kg body-wt respectively. This is much more than effective hypoglycaemic doses in fasted rats (5-10 mg/kg body-wt). The animals appeared healthy but they had slightly decreased rates of weight gain compared with the controls. POCA caused a 15% increase in the weight of the myocardium and accumulation of lipid in the liver. Chronic administration of POCA did not cause any large changes in water-soluble blood metabolite concentrations, although VLDL-triacylglycerol and both VLDL and HDL cholesterol concentrations were lowered. There were only small changes in some metabolites of the glycolytic and gluconeogenic pathways and the citrate cycle in liver and skeletal muscle. ATP concentrations were maintained in all groups. There were 2- to 3-fold increases in the total content of CoA and of carnitine and their acylated forms. POCA-feeding caused small decreases in LPL activities in heart and had variable effects in adipose tissue. POCA was also fed to a few rats on a high fat (30%) diet for 4 weeks. Only small changes in blood, liver and muscle metabolite concentrations were found, except for large increases in the liver CoA and carnitine contents. It was concluded that POCA does not cause large perturbations of glucose homeostasis, or acute toxic effects, during 12 weeks administration to normal animals at high dose levels. The very-long term importance of accumulation of lipid in liver; increase in myocardial weight; and also of hepatic peroxisomal proliferation [A. J. Bone, H. S. A. Sherratt, D. M. Turnbull and H. Osmundsen, Biochem. biophys. Res. Commun. 104, 708 (1982)] cannot yet be determined. The possible use of POCA and related compounds in the chemotherapy of diabetes merits further investigation.
2-[5-(4-氯苯基)戊基]环氧乙烷-2-羧酸乙酯（POCA）在禁食的正常大鼠和糖尿病大鼠中具有很强的降血糖作用[H. P. O. Wolf, K. Eistetter和G. Ludwig, 《糖尿病学》22, 456 (1982)]。将POCA以0.05%和0.2%的水平添加到标准低脂（3%）饮食的大鼠中，连续喂食12周，以使每日摄入量分别约为50和200毫克/千克体重。这远远超过了禁食大鼠的有效降血糖剂量（5-10毫克/千克体重）。这些动物看起来健康，但与对照组相比，它们的体重增加率略有下降。POCA使心肌重量增加了15%，并导致肝脏中脂质积累。长期给予POCA并没有引起水溶性血液代谢物浓度的任何大的变化，尽管极低密度脂蛋白-三酰甘油以及极低密度脂蛋白和高密度脂蛋白胆固醇的浓度有所降低。肝脏和骨骼肌中糖酵解和糖异生途径以及柠檬酸循环的一些代谢物只有很小的变化。所有组的ATP浓度均保持稳定。辅酶A和肉碱及其酰化形式的总含量增加了2至3倍。喂食POCA导致心脏中脂蛋白脂肪酶活性略有下降，对脂肪组织的影响则各不相同。还将POCA喂食给一些高脂（30%）饮食的大鼠4周。除了肝脏中辅酶A和肉碱含量大幅增加外，在血液、肝脏和肌肉代谢物浓度方面仅发现了很小的变化。得出的结论是，在以高剂量水平对正常动物进行12周给药期间，POCA不会引起葡萄糖稳态的大扰动或急性毒性作用。肝脏中脂质积累、心肌重量增加以及肝脏过氧化物酶体增殖的长期重要性[A. J. Bone, H. S. A. Sherratt, D. M. Turnbull和H. Osmundsen, 《生物化学与生物物理学研究通讯》104, 708 (1982)]尚未确定。POCA及相关化合物在糖尿病化疗中的可能用途值得进一步研究。
