Modulation of the stimulatory effect of pregnenolone-16 alpha-carbonitrile on biliary cholesterol output in the rat by manipulation of the rate of hepatic cholesterol synthesis.

In female rats fed a plain ground diet containing pregnenolone-16 alpha-carbonitrile, biliary cholesterol output increased twofold, whereas bile acid and phospholipid output either remained unchanged or decreased slightly. There was a 32% increase in liver weight, a 3.5-fold increase in cholesteryl esters, and a 45% decrease in the rate of hepatic sterol synthesis. When pregnenolone-16 alpha-carbonitrile was fed with AOMA, an agent that blocks cholesterol absorption, there was less of an increase in cholesteryl esters, the inhibitory effect of pregnenolone-16 alpha-carbonitrile on hepatic sterol synthesis was abolished, and biliary cholesterol output was increased to an even greater extent. In contrast, when pregnenolone-16 alpha-carbonitrile was fed together with cholesterol, there was a 14-fold increase in the level of cholesteryl esters, an 85% decrease in the rate of hepatic sterol synthesis, and a marked reduction in biliary cholesterol output. The increase in biliary cholesterol saturation produced by either pregnenolone-16 alpha-carbonitrile alone or pregnenolone-16 alpha-carbonitrile with AOMA occurred with little or no change in plasma cholesterol levels and bile acid pool size. Because biliary cholesterol saturation in rats given pregnenolone-16 alpha-carbonitrile appears to correlate with the rate of hepatic cholesterol synthesis, the drug likely mediates its effect on biliary lipid composition at an intrahepatic level and may provide an important model for determining how overproduction of cholesterol by the body results in excessive transport of cholesterol into bile.