ABSTRACT
Coronary heart disease (CHD) constitutes a major medical problem. In the US, yearly deaths from heart disease outnumber those from any other single disease. The results of numerous clinical studies indicate that lowering serum cholesterol levels reduces the risk of CHD. Initially, it was assumed that all oxysterols regulated 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) through a combination of decreased rates of gene transcription and increased rates of enzyme degradation. The mechanism of cholesterol regulation by oxycholesterols and oxylanosterols in cultured cells also differs with respect to their effects on low density lipoprotein metabolism. In response to the interesting finding that 15-ketone 32 and 15-oxime 33 do not require activation by P-450DM for suppression of HMGR activity, we undertook studies to ascertain the mechanism by which these compounds affect the activity of this important enzyme. The ability of lanosterol analogs to suppress cholesterol synthesis without lowering low density lipoprotein receptor activity suggests that this class of compound may prove to be useful as cholesterol lowering agents.
