Essential fatty acids, isoprostanes, and the origin of life.
Sometimes I rather humorously, and embarrassingly, ask my patients if they remember what was happening while they were in utero. Generally, they don’t recall. The reason I ask, after rephrasing the question (“Has your mom shared with you any difficulties she had when she was carrying you?”), is that I am looking for antecedet factors. Maybe mom was on antibiotics. Maybe she was under a lot of stress. Maybe she drank alcohol or smoked. Maybe she was given the now-recognized teratogen and carcinogen, DES (diethylstilbestrol). All of these are potential influences on my patient’s current presentation, and are thus important questions to explore.
Well, what if we drill down even further. To the time life began. When we were single cells, or even before. Maybe we were just starting to engulf the bacteria that later became the mitochondria… remember? There was just a smidgen of oxygen hanging around, but it was increasing. And along with oxygen came oxidation and free radical formation. We are now a free radical-obsessed culture of functional clinicians. Quenching their formation at every turn. “More antioxidants!” we shout. But back in the day, in this primordial, pre-enzymatic soup, non-enzymatic oxidation fueled important reactions essential to the development of life. And it’s quite plausible that the products of these reactions are still important players in physiology today.
Enter isoprostanes
When I first learned about isoprostanes, non-enzymatically produced before-time-began non-classical eicosanoids, I whispered “ghost eicosanoids.” I was immediately hooked.
Isoprostanes: Ghost eicosanoids? There are likely hundreds of these free-radically formed non-classic eicosanoids secretly going about their business in our bodies; some damaging, but some participating in normal physiology…
You know eicosanoids, of course. I blog about them often, most recently about their influence on testosterone and estrogen, and breast cancer.
Eicosanoids — produced from the COX and LOX enzymes — form a hormone-like signal molecule system of exquisite power and complexity. They are derived from the omega-6 and omega-3 20-carbon fatty acids, and made in every single cell in the body. Eicosanoids from arachidonic acid (AA) are generally, but not always, major players in inflammation; whereas those eicosanoids derived from eicosapentaenoic acid (EPA) and dihomogammalinolenic acid (DGLA) are anti-inflammatory in their (direct or indirect) effects. In general, the goal with our inflamed patients is to reduce the quantity of AA-derived eicosanoids and improve the quantity of EPA and DGLA-derived eicosanoids.
There are hundreds of eicosanoids.
And there are hundreds of isoprostanes. All are produced by free radical action on DHA, EPA, AA and other fatty acids. (Any fatty acid with three or more double bonds can form isoprostanes!) If you consider the complexity of eicosanoid biochemistry, you can get an idea of where we are headed with isoprostane research.
The arachidonic acid-derived F2-isoprostanes are by far the best understood of the bunch. They are similar in structure to the potent pro-inflammatory arachidonic acid-derived PGE2 and PGF2, but exist in much greater quantity. In plasma, F2-isoprostanes are a whopping 10-fold greater than PGF2, and rise considerably higher in those under a great deal of oxidative stress.
F2-isoprostanes are bad actors. They can cause vasoconstriction in the kidneys, lungs, liver, bronchi, blood and lymph vessels, uterus and GI tract. They are associated with increased perception of pain and are elevated in acutely hyperglycemic diabetics. They’re also high in smokers. And heart disease. And autism. In the white matter of the brain of those with early stage Rett Syndrome, a specific isoprostane isomer produced by free radical action on myelin-sourced adrenic acid was found to be up to two orders of magnitude higher than healthy controls, indicating early evidence of brain damage.
More than just biomarkers of oxidative damage, F2-isoprostanes are DIRECTLY damaging. We can readily measure F2-isoprostanes in urine. And we can readily turn production of them around with basic healthy living habits, diet and antioxidants.
But don’t quench all the free radicals just yet: There are other isoprostanes that participate in normal physiology.
Isoprostanes are highest during fetal and early neonatal life. They’re probably important players in development. The placenta is a major producer of isoprostanes.
There are many, many isoprostanes produced by EPA and DHA that have important biological roles. Further, EPA and DHA robustly reduce levels of AA-derived F2 isoprostanes. DHA-derived isoprostanes are cancer-fighting, and certain isoprostane analogues are potently anti-inflammatory.
Fortunately for us, when we’re “back in the trenches” on Monday morning, what we’re going to do with our patients with regards to isoprostanes isn’t too different from what we’ve been doing all along: increasing intake of omega-3 fatty acids, decrease intake of omega-6 fatty acids. Give extra antioxidants if F2’s are high. Nice and straightforward. At least for the time being, anyway. Stay tuned.
Start your journey on isoprostanes here: AOCS Lipid Library