TMP-153, A NOVEL ACAT INHIBITOR, LOWERS PLASMA-CHOLESTEROL THROUGH ITS HEPATIC ACTION IN GOLDEN-HAMSTERS

The mechanism of the hypocholesterolemic action of N-[4-(2- )-6,7-dime lhyl-3-quinolyl]-N'-(2,4-difluorophenyl) urea (TMP-153), a potent acyl -CoA:cholesterol acyltransferase (ACAT) inhibitor, was studied in Gold en hamsters. TMP-153 (0.5-1.5 mg/kg) dose-dependently reduced plasma t otal- and low density lipoprotein (LDL)-cholesterol without affecting high density lipoprotein (HDL)-cholesterol. TMP-153 markedly reduced t he cholesterol influx into the plasma upon intravenous injection of Tr iton WR-1339. The compound also decreased cholesterol absorption calcu lated from dietary intake, biliary secretion and the absorption co-eff icient. Hepatic cholesterol secretion was calculated by substracting t he cholesterol absorption from the cholesterol influx. In hamsters, th e liver accounted for 92% of the cholesterol influx with the remaining 8% coming from the intestine, and both were markedly decreased by TMP -153, Thus, it is likely that TMP-153 lowers plasma cholesterol throug h its hepatic action. In the liver, the compound significantly reduced the unesterified cholesterol content in addition to markedly reducing the content of esterified cholesterol. In accordance with this reduct ion, the half-life time of [I-125]-LDL was significantly shortened by the compound, suggesting an increase in LDL receptors. However, the he patic cholesterogenesis from [C-14]acetate was decreased by TMP-153 tr eatment. This effect seems to be secondary, since the compound did not inhibit cholesterogenesis from [C-14]acetate in HepG2 cells. From the data described above, the contribution of hepatic secretion and intes tinal absorption of cholesterol to the plasma cholesterol level in Gol den hamsters are discussed.