Cholesterol Looks Like Estrogen



For many years, at least the sixties, seventies, and eighties, there were arguments about whether Cholesterol was good for you, or bad for you. This was called, “The Cholesterol Controversy”. There were books written about it, by the same name. Before we go further, cholesterol adorns the cell wall like cloves on a holiday orange. Notice I didn't mention which holiday. The cholesterol molecule is the backbone for hormones that are both useful and important. I won't mention which one either, but all of them is a good start.

As in most controversies, both sides had some truth. There is a “Good Cholesterol" and a "Bad Cholesterol”, just like witches in The Wizard of Oz. Good Cholesterol goes by the name HDL which stands for “High Density Lipoprotein” The bad witch is LDL, which you might have already guessed stands for, “Low Density Lipoprotein”. The good witch, just like in the movie, protects you from the bad witch for reasons that only witches understand. For many years, before I took any prescription, I looked at the scrunched up bit of paper called the product circular. I mainly wanted to see the beautiful little drawing of the molecule that someone took the time to make before they printed the warnings of all the bad things that can happen. Usually I look at the drawing and make up a story to explain it to myself. Before I tell you the story I made up, you should listen to the cooing voices of the Celtic women. I like the sound of Celtic women cooing when I think about “relative binding affinity”. I don’t know why.


Anyway, the story has to do with the fact that the drawings on product circulars look like hieroglyphics and every hieroglyphic has some special meaning. All the rings and side chains do something important.

The Egyptians believed that hieroglyphics were very powerful. They thought if they drew them too perfectly, they would actually crawl off the sarcophagus and start running around. I hope that won’t happen here.



Perhaps I’ve been staring at these structures for too long, but I am starting to see some hidden meaning. There are some things I used to think were very important, that turned out not to be important at all. Other things I used to dismiss turned out to be very important. These affect my cholesterol and your estrogen, and yes, I am hiding behind what is really a very small Y chromosome.


Before I get into that, I have to mention what most people already know, a new class of wonder drugs have been invented to lower my cholesterol. These drugs are from a family of drugs called “statins”. I could provide more detail, but first I want to complain. The first drug I took to lower my cholesterol, Zocor™ made my muscles sore. Zocor™ is also called Simvastatin. Here are the current hieroglyphics:

Zocor™ or Simvastatin in 2-D

Zocor™ or Simvastatin in 3-D


I used to think it was the number, arrangement, and rigidity of the rings and things that was the most important thing. The 3-D picture hints at a more mundane job for the super structure of the molecule. It is to hold the hot spots of the molecule, as in a welder’s jig, in just the right way for something to happen. In this case, it is a couple of oxygen molecules looking for some action.


Lipitor™ or Atorvastatin in 2-D

Lipitor™ or Atorvastatin in 3-D


Not only must the hot spots be held in the right place, but they must bounce around at just the right frequency. And it is this idea of frequency that is so amazing. You see, looking at still drawings creates the unspoken deception that things actually do hold still. They do not of course do that, except at absolute zero. Instead, the structure enables a signature kind of dance number to take place.


But this dancing business is where the trouble really started. Dancing makes my muscles sore. So I called up my doctor who changed my prescription to Lipitor™. I thought I was saved, but then after awhile I found that Lipitor makes my ligaments sore.


Now this gets a little personal, but that’s they way chemistry is, and it actually leads to what I think is an interesting point about the statins, that is also true for other drugs. The point is that their actions or least some of their side effects are tissue specific. Now I don’t happen to know whether this tissue specificity is from the primary intention of cholesterol reduction, or in the fact that the drugs do other things in other places, but I find it interesting. This tissue specific thing I want to develop just a little more before I let it swim away. Speaking of water, I will now mention that the third statin my doctor prescribed. Crestor™ did something completely different. To put it bluntly, Crestor™ makes me pee. The hieroglyphic that follows is the international, time invariant symbol for a full bladder, with the molecular partial charges correctly computed.



Crestor™ or Rosuvastatin in 2-D

Crestor™ or Rosuvastatin in 3-D

The spacing of the hot spots is about the same as in the above, but the sulfur just makes me go. All these drugs work by getting in the way of a special enzyme called HMG-CoA Reductase. This enzyme is at the beginning of a chain of enzymes that perform something called isoprenoid metabolism, which you can Google™.

But forget about my problems. What about the other side?. Consider another family of drugs where tissue specificity is an in issue in la femme Nikita. There is a drug called Tamoxifen that is given to women who have had breast cancer. Tamoxifen, which is estrogen-like binds, to the estrogen receptor. That keeps bad things from happening to good people. It does that in breast tissue anyway. But Tamoxifen has the opposite effect in uterine tissue and muscle. It is almost as good as estrogen.It has a cousin Raloxifene, that doesn’t activate uterine or breast tissue.


Nolvadex™ or Tamoxifen in 2-D

Nolvadex™ or Tamoxifen in 3-D


Tamoxifen also acts as a pseudo-steroid for muscle tissue, increasing strength like a performance-enhancing drug.


Raloxifene in 2-D

Raloxifene in 3-D


It is my bet that the right side chain of Raloxifene doesn’t even make it into the receptor pocket, which is probably why it appears to be a better drug. Note the similarity of the spacing of the twin OH groups of Raloxifene above and Estrogen below.


Estrogen/Estradiol in 2-D

Estrogen/Estradiol in 3-D

Incidentally, there were a spate of young women born in the mid-1950’s who came to be know as “DES daughters”. Their mothers received DES during pregnancy and this caused some developmental abnormalities for some. DES is similar in its configuration to the hormone estrogen, which is also called estradiol or 17B-Estradiol.


DES in 2-D

DES in 3-D


But the question I want to know the answer to is this. Are there specific receptor types that are similar, but distinct in uterine tissue versus breast tissue? Both tissue types are derived from epithelial tissue, but both have a specific function that may trace its way all the way down to the architecture of the cell receptor. That’s my question anyway.

So when we think, “estrogen receptor” should we really be subscripting these receptors by tissue type? That would keep us from thinking that we live in a “one estrogen receptor fits all” kind of a world.

I am fortunate enough to have smart friends. Steve Fliesler has pointed me to the work of Ms. Suparna Saha who discusses the two kinds of estrogen receptor, alpha and beta and their “relative binding affinities” here. ●

 © L. Van Warren 2006