The Rest of the Story

The medical establishment was surprised recently when it was confirmed that cox-2 inhibitors could increase the risk of certain kinds of vascular disease.  Although some prior studies had suggested that this might be the case, the evidence was not strong enough to draw any firm conclusions.  One reason for the skepticism was that there was not any obvious mechanism for such an effect.  A study (abstract, editorial summary) in the most recent issue of the Journal of Experimental Medicine now hints at such a mechanism. 

The structure of resolvin E1, a potent antiinflammatory lipid derived from omega-3 fatty acids.

Although we tend to think of fat as "bad food," humans in fact need fat to survive.  Some kinds of fat are called essential fats, because we need them and cannot make them from simpler compounds.  Most fats can be synthesized in the human body from other foods, such as carbohydrates.  However, we lack the enzymatic machinery to make the so-called omega-3 and omega-6 fatty acids.  Actually, we can only add double bonds to a molecule of fat somewhere in the first nine positions. 

The "omega" part of the name refers to the methyl end of the carbon chain.  Omega-3's have a double bond in the third position from that end.  The COOH group is known in organic chemistry as a carboxylic acid group.  By definition, the carbon atom in the carboxylic acid group is the first carbon atom in the numbering system.  Since a carboxylic acid can contain any number of carbon atoms, the last one is called omega, rather than being given a number.

So why does this matter?  It turns out that the omega-3 fatty acids have several roles in the body.  They also serve as precursors for a newly-recognized class of antiinflammatory lipids: the resolvins. 

This group recently identified a new class of aspirin-triggered bioactive lipids, called resolvins, the activity of which may in part explain the beneficial effects of omega-3 fatty acids. Resolvins are synthesized from the omega-3 fatty acids by cellular enzymes and are potent counterregulators of inflammation in mice. The main bioactive component of this class of lipids was identified in mice and named resolvin E1.

In a study in which volunteers were given low-dose aspirin and fish oil, the researchers were able to find a type of resolvin, resolvin E1 (RvE1), in the blood of the volunteers.  Subsequent studies showed that RvE1 has a variety of antiinflammatory properties.  They suggest that selective cox-2 inhibitors might block the synthesis of RvE1.  Aspirin actually promotes the conversion of a form of omega-3 fatty acid (eicosapentaenoic acid, or EPA) into RvE1. 

This illustrates an important concept.  It is common for early studies to be disregarded because the findings do not fit in with what we know about biochemical mechanisms.  The first study to show an association between Vioxx and vascular disease did not raise much alarm, possibly for this reason.  I am not suggesting that we necessarily should believe the results of studies that contradict our theoretical understanding of how the world works; that would be ridiculous.  However, I do think we need to avoid the trap of immediately rejecting any observations that do not fit our favorite paradigm.

Again donning my Perpetual Sophomore hat -- which has been getting a lot of use, lately -- this leads me to some idle speculation.  What would happen if people who took cox-2 inhibitors also took one baby aspirin (81mg) per day?  Would they get a good effect for arthritis, with less gastric effect than a full dose of aspirin, and with less cardiovascular risk than with the cox-2 inhibitor alone?  And would people who take fish oil for treatment of depression get a stronger effect if they also took aspirin?

Switching to my College Graduate hat, I would have to be skeptical of such conjectures.  Even so, idle speculation can be useful, so long as we do not take it too seriously.  I would not, for example, make any health-related decisions based upon such conjectures; I would consider doing some additional studies ... if I had a Serious Researcher hat.