Eicosanoids

BCH 120 — Metabolic & Endocrine Biochemistry · Dr. Radi

build Jul 17 · 11:11 · CC BY-NC-SA 4.0 · owned figures (RDKit / matplotlib / PyMOL)
Dr. Radi

By the end of this unit, you can…

  • Define eicosanoids as local (autocrine/paracrine) 20-carbon lipid signals, distinguish the families (prostaglandins, prostacyclin vs thromboxane, leukotrienes, lipoxins), and read prostaglandin nomenclature
  • Trace eicosanoid synthesis from arachidonate (PLA₂ release; the COX vs LOX branches) and contrast constitutive COX-1 with inducible COX-2
  • Explain COX inhibitors — NSAIDs/aspirin (irreversible, anti-platelet), selective COX-2 inhibitors and their cardiovascular risk, prostaglandin catabolism, and eicosanoid GPCR signaling
Dr. Radi

Today's route 🗺️

  1. Eicosanoids — Families & Structure
  2. Eicosanoid Synthesis & the COX Enzymes
  3. NSAIDs, Aspirin & the COX-2 Story
Dr. Radi

1 · Eicosanoids — Families & Structure

"Eicosanoids are the body's 'local hormones' — short-lived lipid signals made from a 20-carbon fatty acid that act right where they're born. Learn the family tree, especially the one opposing pair that runs your blood clotting."

Dr. Radi

The "local hormones"

Eicosanoids break the usual hormone rules. They're signaling lipids built from 20-carbon (eicosa-) fatty acids — mainly arachidonic acid — and unlike endocrine hormones, they're not made in a gland and shipped through blood. Instead, nearly every cell makes them on the spot, and they act on the same cell (autocrine) or its neighbors (paracrine), then are degraded within seconds. That local, fast-fading design is perfect for their jobs: inflammation, pain, fever, blood clotting, blood flow, and labor.

Dr. Radi

The precursor and the blueprint

It all starts with arachidonic acid, a 20-carbon fatty acid with four double bonds (20:4), released from membrane lipids. The prostaglandins made from it share a common blueprint: 20 carbons folded around a five-carbon (cyclopentane) ring, with two tails. Two features name each one: the letter (PGA, PGE, PGF…) tells you what's on the ring, and the subscript (PGE₁, PGE₂) tells you the number of double bonds in the side chains — which traces back to the essential fatty acid it came from. Small structural tweaks → big changes in biology.

Dr. Radi

The family — and the great opposing pair

Arachidonate branches into a whole family. The prostaglandins (PGE, PGF) drive inflammation, pain, fever, labor; the leukotrienes run immune responses (LTD₄ constricts bronchioles — key in asthma); and the lipoxins do the opposite, signaling the resolution of inflammation. But the pair to burn in: prostacyclin (PGI₂), from vessel walls, is anti-clotting and a vasodilator, while thromboxane (TXA₂), from platelets, is pro-clotting and a vasoconstrictor. These opposites balance your clotting — and that's exactly what a famous drug class would tip the wrong way.

Dr. Radi

2 · Eicosanoid Synthesis & the COX Enzymes

"Every eicosanoid starts the same way — an enzyme frees arachidonate, then the path forks. The COX fork makes prostaglandins, and COX-1 vs COX-2 is the whole story of the anti-inflammatory drugs."

Dr. Radi

One precursor, two branches

Eicosanoid synthesis is a fork with a gate. First the regulated step: phospholipase A₂ (PLA₂) clips arachidonic acid from a membrane lipid. Then it forks. The COX road (cyclic pathway) makes prostaglandins, prostacyclin, and thromboxane; the LOX road (linear pathway) makes leukotrienes (where some asthma drugs act); and a third, minor cytochrome-P450 branch makes a few more. Beautiful tie-back: corticosteroids block PLA₂, cutting off arachidonate — killing inflammation at its source.

Dr. Radi

COX-1 vs COX-2

The COX enzyme comes in two flavors, and telling them apart is the key to the drugs. COX-1 is the housekeeper — always on (constitutive), quietly protecting the stomach lining and making the thromboxane platelets need to clot. COX-2 is the alarm — normally low, but induced by injury to pump out the prostaglandins of inflammation, pain, and fever (it's up in arthritis, and even in some cancers). That split sets up an obvious drug idea: block COX-2 to kill inflammation while sparing COX-1 to protect the stomach. It seemed perfect — until it wasn't.

Dr. Radi

3 · NSAIDs, Aspirin & the COX-2 Story

"Now the payoff — the drugs. NSAIDs and aspirin block COX; aspirin does it irreversibly and doubles as a blood thinner. And the cautionary tale of the selective COX-2 inhibitors is a perfect lesson in why you can't safely tip a balanced system."

Dr. Radi

NSAIDs and aspirin

The NSAIDs — non-steroidal anti-inflammatory drugs like ibuprofen and aspirin — all work by blocking COX, cutting prostaglandin production to relieve pain, fever, and inflammation. Aspirin is the special one: it irreversibly acetylates COX (hitting COX-1 more), so it also shuts down platelet thromboxane — making it an anti-clotting drug. That's why low-dose aspirin prevents heart attacks and strokes. The catch is the flip side of COX-1: because that enzyme protects the gut, blocking it causes stomach ulcers and bleeding — and because prostaglandins also maintain renal blood flow, NSAIDs can impair kidney function. (And never give aspirin to a child with a viral illness — Reye's syndrome.)

Dr. Radi

The COX-2 inhibitor lesson

One of pharmacology's great cautionary tales. The idea was elegant: hit only COX-2 — killing inflammation while sparing COX-1 and the stomach. The "-coxibs" (celecoxib, rofecoxib/Vioxx) did just that. But post-approval data showed a jump in heart attacks and strokes, and Vioxx was pulled in 2004. Why? Blocking vessel COX-2 drops prostacyclin (anti-clotting) while platelet thromboxane keeps going — tipping that opposing pair toward clotting. You can't safely knock out one side of a balanced system.

Dr. Radi

Ending the signal, and reading it

Two last pieces close the loop. Catabolism: eicosanoids are meant to be short-lived, so prostaglandin dehydrogenase (PGDH) inactivates them fast — locally, or in a single pass through the lungs — which is what keeps their action local. Reception: they act through prostanoid GPCRs (the EP1–EP4 family and others) on the same or neighboring cells. And here's the elegant part — depending on which receptor a tissue expresses, the same prostaglandin can raise or lower cAMP, or fire IP₃/Ca²⁺ — so one molecule produces opposite effects in different tissues. Fast to clear, flexible to interpret.

Dr. Radi

Can you…?

  • ☐ define eicosanoids as local (autocrine/paracrine) 20-carbon lipid signals, distinguish the families (prostaglandins, prostacyclin vs thromboxane, leukotrienes, lipoxins), and read prostaglandin nomenclature?
  • ☐ trace eicosanoid synthesis from arachidonate (PLA₂ release; the COX vs LOX branches) and contrast constitutive COX-1 with inducible COX-2?
  • ☐ explain COX inhibitors — NSAIDs/aspirin (irreversible, anti-platelet), selective COX-2 inhibitors and their cardiovascular risk, prostaglandin catabolism, and eicosanoid GPCR signaling?

If any box stays empty, the practice site has a drill for it. 🧪

Dr. Radi