New Cholesterol-Lowering Drugs May Lack Statins' Side Effects

A new generation of cholesterol-lowering drugs may be based on inhibitors of the enzyme squalene monooxygenase.

The current drugs of choice for reducing cholesterol levels, the statins, act by blocking the activity of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). Although statins are quite effective at reducing cholesterol, they are associated with potentially severe side effects such as intense muscle pain. These side effects may be due to the fact that blocking HMGR disrupts cholesterol production very early in the metabolic process. Squalene monooxygenase, on the other hand, forms a checkpoint much farther down the pathway where it uses NADPH and molecular oxygen to oxidize squalene to 2,3-oxidosqualene (squalene epoxide). At this point, it catalyzes the first oxygenation step in sterol biosynthesis, and is thought to be one of the rate-limiting enzymes in this pathway.

Another important point stressed in a paper published in the March 1, 2011, issue of the journal Cell Metabolism was that the activity of squalene monoxygenase was regulated by cholesterol itself and not by reaction byproducts or cofactors.

"Cholesterol has developed something of a bad name; so many people do not realize that it is actually essential for a healthy body. It is needed, for example, to make sex hormones and to help build the walls of every single cell in our bodies,” said senior author Dr. Andrew Brown, professor of biotechnology and biomolecular sciences at the University of New South Wales (Sydney, Australia). "The class of drugs most commonly used to lower cholesterol - statins – are the blockbusters of the pharmaceutical world and work by inhibiting HMGR. But HMGR is involved very early on in the assembly line, so inhibiting it affects all the other steps down the line – and other useful products it provides - and that can give rise in some people to unwanted side-effects, such as muscle pain.”

"What is exciting about this previously overlooked squalene monooxygenase enzyme is that it acts as a checkpoint much further down the assembly line, which should mean that it can be more specifically targeted at cholesterol production instead and leave the early part of the assembly line undisturbed,” said Dr. Brown.

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University of New South Wales