Antioxidants against cholesterol

The enzyme HMG-CoA reductase (HMGR) catalyzes the rate-limiting step in cholesterol biosynthesis. HMGR has been closely studied and hotly targeted by pharmaceutical designers; it is famously the target of the family of cholesterol-lowering drugs known collectively as statins — one of which, Pfizer’s flagship Lipitor, is the top-selling prescription medication in the world.

Elevated HMGR can cause hyperlipidemia, which is co-morbid with a host of late-life disease including atherosclerosis, stroke and even cancer. It is therefore discouraging to learn that HMGR levels increase during aging — this may explain why hypercholesterolemia, although under significant genetic influence and therefore latent in an individual throughout the lifespan, takes a few decades to manifest itself. In a rat liver model, the rise in activity appears to occur in response to high levels of reactive oxygen species (ROS); a new paper by Pallattini et al. describe the regulatory biology of this phenomenon and argue that the ROS effect on HMGR activity is mediated via the p38/MAPK pathway.

This suggests the benefits of antioxidant therapy in conjunction with HMGR inhibition — but why take two pills when you can take only one? Ajith et al. report that the compound rosuvastatin (AstraZeneca’s Crestor) is both a potent HMGR inhibitor and an antioxidant. The antioxidant activity is narrow-spectrum, apparently specific for hydroxyl radicals but with no effect on superoxide; nonethless, it significantly protects against oxygen-induced DNA damage as well as lipid peroxidation.

I’d be very interested to know whether rosuvastatin’s antioxidant action inhibits the age-related increases in HMGR levels in the rat liver model studied in the Pallatini paper. If so, compounds of this kind could provide a potent “one-two punch” against late-life hyperlipidemia and its associated diseases.