Effect of AMO 1618 on cholesterol and fatty acid metabolism in chickens and rats

Abstract

AMO 1618 (2-isopropyl-4-dimethylamino-5-methylphenyl-l-piperidine carboxylate methyl chloride) was added to corn-soy based diets and fed to 9-week-old female chickens for 3 weeks to measure the inhibition of hepatic β-hydroxy-β-meth-ylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7α-hydroxylase. Dose-related decreases in the activities of these two enzymes were obtained (2.5–15 ppm) of AMO 1618. Decreases in plasma total cholesterol, chol-HDL, and chol-LDL levels were observed, but the decreases in chol-LDL were substantially larger than those of chol-HDL in both chicken and rat. Assays of livers from rats fed 20 ppm AMO 1618 for 3 days had 24% less HMG-CoA reductase activity and 67% less cholesterol 7α-hydroxylase activity than the controls. Plasma cholesterol in these animals was reduced 26%; the ratio of total cholesterol: chol-HDL was reduced from 3.27 to 2.67 and the chol-LDL : chol-HDL ratio was reduced from 1.96 to 1.14 as a result of the relatively brief treatment. Fatty acid synthetase (FAS) and other key lipogenic enzymes increased 1.5-4-fold in both the chicken and rat. The inhibition of HMG-CoA reductase and the induction of FAS by AMO 1618 were tested in vitro, using 10–100 μg (28–280 μmoles) for 15 min with isolated hepatocytes from chicken and rat. Linear responses in activity were dose-dependent and increased with duration of incubation (30 μg or 85 μmoles AMO 1618, 5–120 min) in both species. The results suggest the compound acts at the cellular level and AMO 1618 appears to possess several properties which recommend it for testing as a cholesterol-lowering agent in humans.