Anti-Inflammatory Diet

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Anti-Inflammatory Diet and Lifestyle.
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Thursday, January 8, 2009

There Is More Than Antioxidants

Every time a plant product has an impact on a disease it seems to be attributed to its antioxidant activity. Plant products are active, because they bind to proteins. They bind to lots of different proteins.

Krill oil is a good example. The anti-inflammatory activity of krill oil is due to its omega-3 oil (DHA and EPA) content, but krill oil is more potent than expected. Krill oil also contains a terpene, astaxanthene, that is probably derived from its algae diet. Astaxanthene is labeled as an anti-oxidant, but that is much too easy.

Astaxanthene consists of two flat, hydrophobic paddles, connected by a flexible, hydrophobic chain. Those paddles are important, because of their inability to hydrogen bond with water, i.e. hydrophobicity, and therefore their propensity to get stuck in contact with other hydrophobic surfaces. The list of candidate hydrophobic surfaces includes the obvious smaller aromatic rings (e.g. phenylalanine), indole double rings (e.g. tryptophan), and the less obvious sugars (e.g. galactose), unsaturated lipid/prostaglandins and basic amino acids (lysine and arginine). These are dominant cellular interactions.

The interchangeability of the hydrophobic paddle-binders means that astaxanthene can get its paddles stuck in enzyme or receptor protein active sites that normally bind a wide range of ligands (target small molecules, e.g. enzyme substrates). It is likely, therefore, that astaxanthene has anti-inflammatory activity, because it blocks an inflammatory interaction.

The ubiquity of interactions of terpenoids, based on their general structural properties, also gives these molecules access to cellular cytoplasm. These molecules are too large to diffuse through membranes and if they got half way through, they would be permanently stuck in the membrane. Terpenoids will tend to stick to carrier proteins that have hydrophobic patches or slots. These carriers will transport and internalize terpenoids and other similarly shaped molecules, e.g. steroid hormones.

Metformin, the diabetes drug, is another example of a molecule with a flat, hydrophobic side. It is a stretch to call this an antioxidant, but it is useful for this discussion, since one of my students tested to see it it would stick to a tryptophan in the active site of a classic enzyme, beta-galactosidase. Galactose, in the typical substrate for this enzyme, lactose, will bind to the active site, because of a prominent tryptophan. The shocker is that my student showed that metformin also binds to that same site and competes with lactose. Astaxanthene would also be expected to bind in the same way.

Curcumin is one of the most potent anti-inflammatory compounds and the main ingredient in turmuric, binds to proteins that inhibit the inflammatory transcription factor, NFkB. I would expect astaxanthene to also inhibit NFkB.

Capsaicin is a related molecule that binds to the heat/pain sensor in skin and blocks pain sensation. That is how capsaicin is used as a topical analgesic. Castor oil, ricinoleate, binds to the same sensor and competes with capsaicin and also is an effective pain reliever. Note that ricinoleate is a modified fatty acid that could curl up on the same hydrophobic paddle surface as capsaicin.

The bottom line of this discussion is that if someone tries to convince you that resveratrol, the anti-aging ingredient in wine, is an anti-oxidant, be skeptical. Expect that resveratrol will have numerous interactions with proteins and many of those will not be known.

2 comments:

Stephan said...

Great post. Antioxidant mania has taken over the health/nutrition field and it's ridiculous.

I remember seeing a presentation on curcumin and alzheimer's at a conference, I think it was by Dr. Greg Cole. I can't seem to find the notes right now, but the jist was that the effect was not due to its antioxidant properties, but to its drug-like effect on signaling pathways.

Polyphenols don't contribute significantly to the antioxidant potential of serum. Our serum antioxidants are primarily uric acid, vitamin C and vitamin E, with little to no contribution from these supposedly wonderful vegetable antioxidants. The increase in serum antioxidant capacity seen after ingesting certain plant foods is actually the result of increased serum uric acid! Often it's due to the fructose. You can get the same effect by drinking a Pepsi.

George Henderson said...

True, but there are exceptions; betalains from beetroot (indole derivatives - those paddles again) reduce oxidation of lipoproteins.
And the beta-carbolines in chocolate and garlic - tetrahydroxy-indoles, paddles again - might be potent antioxidants.
And oligomers might act differently from single polyphenols.
Or not - who knows yet?