FEATURE ARTICLE
Statins: From Fungus to Pharma
The curiosity of biochemists, mixed with some obvious economic incentives, created a family of powerful cardiovascular drugs
Philip A. Rea
Cholesterol's Complexities
Before further examining the history of the statins, it is instructive to consider a perplexing question, or at least a question that is perplexing with the benefit of hindsight. That is, if statins diminish all types of cholesterol, why do they reduce the risk of cardiovascular diseases? Surely, a block on cholesterol production should decrease both the good and the bad, the HDLs as well as the LDLs. Well, the short answer to this question is: Luckily, these drugs are more selective than could have been anticipated when they were first discovered.
The empirical results speak for themselves. Treatment with statins does appreciably decrease LDLs, as expected. But, in addition, statins increase HDLs, and by more than 7.5 percent, according to some studies.
The liver is the hub when it comes to LDLs. When the production of cholesterol in liver cells is diminished by the inhibition of HMG-CoA reductase, fewer LDLs enter the circulation. And because the liver cells have fewer LDLs entering to contribute to the cholesterol pool, they generate more LDL receptors on their surfaces to grab more of this substance from the blood. The combination of producing less cholesterol in general—including the LDL fraction—and pulling more LDLs from the blood into liver cells serves to deplete circulating levels of LDL cholesterol. All other things being equal, high numbers of LDL receptors in liver cells equate with low levels of LDLs in the blood.
All well and good, but if a statin decreases the overall production of cholesterol, shouldn't circulatory HDL levels also decrease? Logically they should, but fortunately they don't. Instead, circulatory HDLs increase, making statins even more cardioprotective than they might otherwise be.
Currently, there is no consensus on just how statins increase blood HDL levels. Some scientists suspect that statins inhibit the transfer protein responsible for unloading the cholesteryl ester cargo of HDLs. A variety of experiments on animals and humans show that blocking the cholesteryl ester transfer protein triggers increases in the levels of HDLs. Another possibility is that statins stimulate the expression of HDL transport proteins, which in turn ferry this form of cholesterol from the liver to the blood.
It is intriguing to consider that the mechanisms that nearly stalled Endo's first screens of mevastatin, because they were done on rats, are the very mechanisms that make these drugs so effective therapeutically in humans. Rats are an exception because their steady-state blood levels of LDLs are low; most of their blood cholesterol is in HDLs. What this means is that even if statins decreased blood LDL levels enough to be noticeable in the short term in rats, any long-term effects at the level of total blood cholesterol would be offset by a subsequent increase in HDLs. As Endo's work with chickens and subsequently other animals (including humans and other primates) was to show, a lowering of total blood cholesterol is typically seen because LDL cholesterol ordinarily represents a sizeable fraction of the total—a much larger fraction than in rats and other rodents. And to think that egg-laying hens were to pave the way for the use of statins in humans.
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