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Fighting high cholesterol

New drugs reduce cholesterol by inhibiting a key enzyme used to manufacture it

By a cruel twist of fate I was born loving steak, a 1 1/2 inch Porterhouse my idea of culinary perfection. What is cruel about this is that a few years ago my doctors informed me I have high levels of cholesterol in my blood, well over the upper recommended level of 190. Because all this cholesterol in my blood tends to deposit itself along the insides of arteries, this puts me at high risk of heart attack if I don't do something about it.

Thus began my long battle with cholesterol. My old friends peanut butter, cheddar cheese, and french fries became history, steak a much more casual acquaintance. My wife and three daughters, knowing my weakness of character when it comes to things bovine, started to do more of the grocery shopping, buying lots of chicken.

Didn't do any damn good. All those steakless nights, and my cholesterol levels rose higher than before. When last measured in October, my total cholesterol was 274, the highest its ever been. When you consider that every 1% increase in level over 190 increases my risk of heart disease 2%, the October report was frightening.

I called my brothers to report the bad news, only to find that they too wage the same battle. The problem, it appears, is that I and my brothers inherited a defective steak-hating gene. We suffer from hypercholesterolemia. This mouthful of a word simply means inherited high cholesterol. People inheriting a copy of the defective gene from one of their parents have elevated levels of cholesterol in their blood serum which dietary restriction (taking away my steaks) cannot reduce.

My frustrating on-going battle with cholesterol is not unique. Over half a million Americans suffer from hypercholesterolemia, the most frequent of all gene disorders. None of my hundreds of thousands of brothers and sisters in this war, fellow victims of this genetic quirk, are able to reduce cholesterol levels by diet and exercise alone. They, and I, must rely on modern medicine to defeat our Mendelian enemy.

Even a quick look at the biology of cholesterol suggests a likely line of attack. Cholesterol is a special kind of fat that your body uses to control the flexibility of its cell membranes and to insulate nerves. Your liver makes about 80% of the cholesterol in your body, up to 800 mg. a day. You take in the rest when you eat steak and other fatty foods

You can see why my attempting to lower total cholesterol by reducing dietary input of fat (steaks, peanut butter, fried food, chocolate, ice cream-- all the good stuff) didn't get the job done. Dietary cholesterol is only 20% of my body's total. Most is manufactured by my liver, and because of hypercholesterolemia, my liver is churning out

cholesterol twice as fast as a normal liver does. To solve the problem, I need to put the breaks on my liver's cholesterol-making frenzy.

In the 1980s researchers determined that the rate-limiting step in the liver's manufacture of cholesterol occurs early in the process, when a 6-carbon molecule called mevalonate is converted to something called hydroxy methyl glutaryl CoA (HMG-CoA, for short). This reaction is carried out by an enzyme called HMG-CoA reductase. If we want to slow cholesterol production, that's our target.

In the last ten years a series of drugs called statins have been developed that reduce levels of cholesterol by inhibiting HMG-CoA reductase. Among them are fluvastatin (Lescol), lovastatin (Mevacor), simvastatin (Zocor), and pravastatin (Pravachol).

The newest member of the pack, introduced just two years ago, is atorvastatin (Lipitor). Lipitor is a particularly potent inhibitor of HMG-CoA reductase with fewer side effects than other statins. Developed by Warner-Lambert and marketed by Pfizer, lipitor is a blockbuster drug. It is expected to generate $4.4 billion in sales next year, and to be the top-selling global drug by 2005, with sales as high as $10 billion.

It is upon lipitor that I am banking my future. I started taking it last week. It is likely that if lipitor works for me, I shall be taking it the rest of my life.

In THE NAMING OF CATS, the T.S.Eliot poem on which the broadway musical CATS is based, "a cat must have three different names." I think of my new anticholesterol drug as being like T.S.Eliot's cat. Like his cat, my drug has a "sensible everyday name", lipitor, a name which anyone can use. Then Eliot says a cat needs a second name, "a name that's particular", "a name that never belonged to more than one cat." Pravastatin is such a name, one that drug manufacturers and scientists use.

According to T.S. Eliot, every cat also needs a third very private name, a "deep and inscrutable singular name." For lipitor, this name, its chemical soul, is [R-(R*,R*)]-2-(4-fluorophenyl)-B,d-dihydroxy-5- (1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] -1H-pyrrole-1-heptanoic acid.

To someone looking at a cholesterol level of 274, that's beautiful.

©Txtwriter Inc.





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