Metabolic changes in fed rats caused by chronic administration of ethyl 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate, a new hypoglycaemic compound.

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.