geddarkstorm -- A metabolite of quercetin is a Sirt1 inhibitor. Despite it's other benefits, it should perhaps not be used with resveratrol.
Actually, I'm not all that convinced about that. There is only one paper, which I'll have to go to lab to get full access to, but they did not see inhibition of Sirt1 in vitro cells, only inhibition of their recombinant Sirt1 from the sound of it. Quercetin had no effect on the in vitro cells. That is, it's stated:
SIRT1 stimulation by polyphenols is affected by their stability and metabolism.
de Boer VC, de Goffau MC, Arts IC, Hollman PC, Keijer J. Mech Ageing Dev. 2006 Jul;127(7):618-27. Epub 2006 Apr 17.
"Using metabolically active HT29 cells we were able to show that quercetin (a stimulator of recombinant SIRT1) could not stimulate intracellular SIRT1. The major quercetin metabolite in humans, quercetin 3-O-glucuronide, slightly inhibited the recombinant SIRT1 activity which explains the lack of stimulatory action of quercetin in HT29 cells."
When I go into lab again tomorrow, I'll grab the full paper and tell you what they really saw. But notice, in the abstract, that quercetin activated the recombinant Sirt1 outside of a cell, but didn't the Sirt in the cells, and then its metabolite slightly inhibited recombinant Sirt1 which is part of their a-cellular assay from the sounds of it? (not sure, again have to get the paper), and in the end, there was no net effect of Sirt1 intracellularly from what it sounds like the abstract says. Furthermore, we know that recombinant Sirt1 assays are misleading as resveratrol is seen to directly interact with recombinant Sirt1 having a fluorophore, but not directly interact with native Sirt1 (that is, resveratrol's molecular mode of action doesn't appear to be direct binding and activation to Sirt1, or at least it doesn't seem clear from the studies I've read. There's intracellular pathways to activate Sirt1's various roles after all and resveratrol may activate an upstream effector that then turns on Sirt1). And even more, Sirt1 does have various rolls, so which roll would quercetin be inhibiting? This isn't even in vivo, which may change things yet again, and I've seen two papers so far that say quercetin activates Sirt1 in more complex systems (one I'll be referencing later). I really need that paper..
Still, even if quercetin's metabolite mildly inhibits Sirt1, the great increase in Sirt1 given by resveratrol while quercetin is being metabolized is probably all that's needed in theory, as activation of Sirt1 even transiently can lead to the deacylation of the PGC-1 gene, and it is that gene's transcription that gives all the beneficial effects of resveratrol seen to date. In other words, studies where the PGC-1 gene was modified so it could not be deacylated by Sirt1 resulted in resveratrol having no effect on cell metabolism and gene expression. Conversely, putting in PGC-1 which was always deacylated gave the same effects as seen by resveratrol (PMID: 17112576). So, resveratrol acts through the Sirt1 pathway to turn on PGC-1 and that is where we see our benefits. Sirt1 doesn't have to be on long, which is why even though resveratrol has a half life of ~14 minutes (3 hours with quercetin?), it is till long enough to activate Sirt1 to turn on PGC-1. That's why I'm a little skeptical that quercetin interferes with resveratrol to a significant extent till I see more evidence, especially in vivo.
On the other hand, quercetin affects other pathways, such as MAPK's. The effects you have when taking it may be due to its other functions, not interference with resveratrol, per ce. For instance, quercetin increases the expression of Bone sialoprotein which is implied to nucleate hydroxyapatite crystals in mineralized connective tissues (PMID: 17243115). Depending on the source of your joint pain, that could be a reason it increases it, by increasing calcium crystal formation. On the other hand, for other people, quercetin and its main metabolite (which is the sulfated version, not the glucuronidated form according to this paper) inhibits the inflammatory eicosanoid leukotriene B4 (PMID: 18096136), a powerful inflammatory mediator that may play a role in a lot of arthritis and other pains, along with other inflammatory eicosanoids. So, if that was the source, then quercetin would be expected to help. Nothing can be ruled out of course, and different cell lines and biochemistries may respond differently to the combination, and the two at once may have more effects than either alone. It would be interesting to know if quercetin by itself when not taking resveratrol affects your level of joint pain in any way, and maybe that will help tease this issue apart.
Also, take a look at this paper:
Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults.
Okawara M, Katsuki H, Kurimoto E, Shibata H, Kume T, Akaike A. Biochem Pharmacol. 2007 Feb 15;73(4):550-60. Epub 2006 Nov 9.
"Notably, resveratrol activates sirtuin family of NAD-dependent histone deacetylases implicated in regulation of various cellular processes including gene transcription, DNA repair and apoptosis. Here we examined neuroprotective effect of resveratrol on dopaminergic neurons in organotypic midbrain slice culture. Resveratrol and quercetin, another sirtuin-activating polyphenol, prevented the decrease of dopaminergic neurons and the increase of propidium iodide uptake into slices induced by a dopaminergic neurotoxin 1-methyl-4-phenyl pyridinium (MPP(+))."
Albeit, this isn't working with the metabolites of either, and I don't know if the neurons would metabolize them, so definitely take it with a grain of salt - the quercetin may not even have had its protective effects via Sirt1 but some other mechanism. It still paints a complex picture as here's a cell line that displays benefits from both resveratrol and quercetin. Everywhere I look, the story is painfully complex for all these compounds...
EDIT: Holy moly this is terribly off topic.. sorry.
Edited by geddarkstorm, 01 December 2008 - 10:12 PM.
