The statin class of cholesterol-lowering agents is rich with history and lessons in the power of natural products, the potential of the prepared mind, and just how precarious the path of drug development can be.
Expertly and engagingly written by University of Pennsylvania biology professor Dr Philip A Rea, the article launches with the story of a then-young Japanese biochemist, Akira Endo. (Evidence of my longstanding admiration for Dr Endo goes back beyond my 10 Jan 2006 post, "All hail, Dr Akira Endo.").
As we shall see, Endo's two interests--fungi and cholesterol--merged and spurred the discovery and development of a group of cholesterol-lowering drugs called statins. The number of deaths from cardiovascular diseases has decreased by about 25 percent in the United States since 1994, not because of a radical change in lifestyle--though this is happening--but because of the ready availability of cardioprotective drugs. Of the handful of drugs out there that have fought cardiovascular diseases, statins are right at the top of the list.
Don't get me wrong - it's not all glamour and uncritical aggrandizement. Rea provides a sober assessment of the promise and problems of statins, including the controversial ads featuring Dr Robert Jarvik.
The problems of statins are not at all insignificant, particularly due to muscle pain and potentially fatal rhabdomyolysis. The latter condition, while rare, can cause muscle tissue to break down and release myoglobin, the oxygen-carrying protein of muscle. Myoglobin release can cause kidney failure and while this effect is rare, a drug given to millions of people is likely to have very severe side effect in a few dozen people. PharmMom has also had problems taking her statin because of muscle weakness this is uncomfortable, but not dangerous.
A recent pharmacogenetic study published in New England Journal of Medicine reveals that individuals predisposed to statin-induced myopathies harbor polymorphisms in the SLCO1B1 gene. This gene product encodes an organic anion-transporting protein in the liver that has been associated with statin uptake into the liver; the polymorphisms in the gene appear to lead to a less-efficiently acting transporter that increases statin levels in the blood (relative to people with the "reference" or normal gene who are taking the very same dose of statin), causing greater concentrations to be available to muscle.
A previous hypothesis was that statins caused reductions in the muscle mitochondrial content of ubiquinone or Coenzyme Q10, an important part of the ATP-producing electron transport chain that employs the same precursor molecules as cholesterol. However this hypothesis did not account for the reason why only a small subset of patients experiences muscle weakness with statins or why an even smaller subset experienced rhabdomyolysis.
As I write this, I realize that the NEJM paper will likely require another separate post to do justice to the report.
So, back to the wonder of scientific research and the contribution of natural products to lifesaving therapeutics: go read Dr. Rea's article in American Scientist. It's Friday night in the continental US so grad a fine beverage and enjoy some excellent science writing.