I believe niner has elucidated a major cause of "joint" pain with this post: Interaction with other drugs and/or supplements, involving CYP 3A4 and 2C9 mechanistic inhibition which can lead to myopathies manifested as tendinitis or joint pain.
Yes, this gives us a clear 5th possibility, and one that immediately addresses tendinitis rather than just joint based pain. We should be able to test this rather easily, but painfully, regrettibly, so I can't ask anyone to do this, by using factors that specifically target the CYPs, such as grapefruit. Those CYPs aren't just doing nothing in the body 
.
Individual variability in phenotype and amount of these enzymes will complicate this. I'd expect Japanese and some other east Asians to be particularly sensitive/
Fortunately that too is something easily tested. Perhaps if we added ethnicity to any questionnaire about resveratrol/quercetin/pomegranate associated pains, we could get an ethnic distribution which would answer this assumption nicely.
There is still a problem we have though - tendons are not muscles (different cell types and everything), and myopathy (myocyte problems) does not equal tendinitis, technically, but tendinopathy would (tenocyte problems). We see this distinction reflected in the literature.
The biggest conceptual challenge that remains (for me) is how would these factors, or inhibition of CYP3A4, affect tendons? The vast majority of tendinopathy is caused through
strenuous activities and misloading of force on the tenocytes. The exact mechanisms underlying tendinopathies like tendinitis are still largely unknown, but friction rubbing is one major explanation kicking around, related to the two above, where a loss of a smooth gliding surface happens. This also is part of the explanation for why arthritis typically can lead to tendinitis, as the inflamed joint area rubs on the tendon, leading it to inflame too. How in the world would inhibiting CYPs affect tenocytes at all, since CYPs only are involved in the metabolism of mostly xenobiotics, so it would take the loss of the metabolism of some factor, and then that factor going on to affect tenocytes for this link to be possible - so there is somewhere we need to look, and at least we can test with grapefruit juice which is low in quercetin but directly inhibits CYP3A4 quite potently, so we can tease the two apart and investigate CYPs.
However, we may have a lead. We see that tendinopathy (including tendinitis) can be caused by certain drugs like Ciprofloxacin (a broad spectrum antibiotic), and
other fluoroquinolone antibiotics. It does so possibly by
inhibiting tenocyte migration and causing
oxidative stress damage. Ciprofloxacin is also interesting in that its method of antibiotic action is very similar to quercetin's:
both inhibit DNA gyrases (which only bacteria have). Since they have similar antibiotic activities, could quercetin and ciprofloxacin affect tenocytes in similar ways? Quercetin is an antioxidant, but like all antioxidants, including resveratrol, a large dose can become pro-oxidant, and these effects manifest at times as pain in the joints. Still, there's no proof that quercetin affects tenocytes, even with all the numerous studies in humans at 1gram doses, but at least there's a possibility due to its likeness with ciprofloxacin in at least one molecular role. What about pomegranate, though?
How then would resveratrol also do this? It isn't known to affect DNA gyrases or act as an antibiotic like quercetin, so already there is a functional difference which attenuates its chance to do the same effects in tenocytes as ciprofloxacin. Could it be some pro-oxidant activity at high doses? Except, the dosage required would be far beyond what can be attained in vivo, theoretically (100s of micromolar range). Though, bioflavanoids will add to each other, so resveratrol plus quercetin will have a synergistic dosage effect (due to quercetin blocking resveratrol metabolization), and one cannot just add the contributions of either together.
So far my searching for a cause is coming up empty. So little is known as to how tenocytes can be affected adversely and lead to tendinopathy. There is also the possibility that resveratrol induced bone density growth could play a role, as calcification can lead to tendinopathy if it occurs too rapidly (friction rubbing and loss of a smooth gliding surface, again). But this seems unlikely, as it would be the norm not the exception if it were the case (unless the people who experience tendinitis have thin bones to begin with, so the density increase for them is more dramatic).
On a final, very very important note that I would like to reiterate from above:
tendinopathy (including tendinitis)
is not the same as myopathy (muscle pain) or
chondropathy (joint pain).
Tenocytes (tendon cells)
are not the same as myocytes (muscle cells) or
chondrocytes (joint cells). More often than not, factors that effect each cell type are different, factors that lead to each pathy are different, and the treatments for each are different.
This is absolutely crucial for everyone to keep in mind. Depending on what type of pathy we are dealing with, the rules and treatments for are most likely different, though there is always a chance they are the same (i.e. statins can affect myocytes and, to a lesser extent, tenocytes). Also, if we are to scan through the literature wisely and not just flail about blindly, we need to know what we are looking for (and what cell type). Please, everyone, keep this in mind. There can be instances of interrelation, but it is in the sense of indirect symptoms from the true pathy source rather than multiple pathy's, more often than not. So, until we know exactly which pathy we are dealing with, or combination of pathy's as resveratrol or other factors could still cause more than one type in different people, and it could be different for different people, we can't proceed with recommending an "antidote" with any confidence. We can only keep investigating and trying to narrow down which one(s) it is.
Edit: Hmm, because
statins can cause tendinitis, and are metabolized by CYP3A4, which resveratrol could potentially inhibit at higher doses, I would like to know, if anyone is willing, if those who experienced the tendon/joint pain on resveratrol were taking a statin of any kind, statin mimic, or otherwise statin like drug/supplement.
Edited by geddarkstorm, 25 February 2009 - 09:57 PM.
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