I appreciate your contributions as well. I had a feeling that this was going to ruffle some feathers so I'm happy to address each of your points...
Jmorris your contributions on the forum are educated, valuable and appreciated, but lets not forget that the Human Equivalent Dosage (HED) of 30 mg of Dasatinib and 300 mg of Quercetin still somehow had the desired effect in mice... Why..?
http://www.longecity...ndpost&p=722108
(NB that this link is to a local senolytic thread!)
As Nate has already pointed out, mice and rats both don't metabolize quercetin like humans do. I'll leave it at that.
"...Quercetin glucuronide can apparently get converted back locally into free quercetin aglycone, at inflammation/mitochondrial dysfunction sites, with help from macrophages..."
http://www.longecity...ndpost&p=722812
(Thx! DeadMeat)
ie: Quercetin Glucuronide seems to be converted into Quercetin Aglycone exactly where we want it; the senescent cells with their inflammation and dysfunctional mitochondria!?
This reference is to the following paper:
J Clin Biochem Nutr. 2014 May;54(3):145-50. doi: 10.3164/jcbn.14-9. Epub 2014 Apr 12.
ß-Glucuronidase activity and mitochondrial dysfunction: the sites where flavonoid glucuronides act as anti-inflammatory agents.
Kawai Y.
Looking at the paper, I see that they are hypothesizing "that macrophages could be the major target of dietary flavonoids in vivo."
Macrophages are secreting β-glucuronidase which presumably converts querctin back to its bioactive aglycone form. They state that this requires an acidic pH.
"Surprisingly, the quercetin aglycone and the methylated quercetins (3'- or 4'-methylated quercetins), as well as Q3GA itself, were significantly detected in the Q3GA-treated RAW264 cells.(23) The generation of quercetin and methylquercetins from Q3GA reflects the presence of the enzymatic activities of β-glucuronidase and COMT in the macrophages. These non-conjugated derivatives were also detected in other lines of macrophage cells (J774-1, differentiated THP-1 and peritoneal primary macrophages) upon treatment with Q3GA, but not detected in the vascular endothelial cells (HUVEC and BAEC) and many other cell lines from different tissues."
So the quercetin is getting converted to the agylcone and then diffusing back somehow into the macrophage (RAW264 cells). But, note that the aglycone is not detected in any other cell type. This paper would have been much better had they detected it in other cells so I suspect some poor graduate student spent his or her summer failing at this.
Next, they state:
" The in vivo expression of β-glucuronidase is also demonstrated immunohistochemically in the foamy cells in atherosclerotic aorta of the apoE-deficient mice (Fig. 2), showing the tight link between inflammation and the deconjugation in vivo."
They can say this is "showing the tight link" as much as they want, but since they never detect the aglycone in these tissues I'm not sure why they are mentioning it at all. In my mind it weakens their case rather than the opposite. They also mention some stuff about how β-glucuronidase is expressed in cells that have dysfunctional mitochondria. So what? How exactly is glycosylated quercetin going to get into the cells for that to be any use? Answer: It doesn't, which is why they did not detect it in any other cells.
What I am getting from this paper is that the authors believe that quercetin aglycone is present inside of rodent macrophages due to the processes that they describe and that it might have an effect on those macrophages.
Okay. That's interesting.
What you seem to be saying (please correct me if I am wrong, I don't mean to offend) is that somehow this means that quercetin aglycone will be available in human senescent cells somehow.
How?
Can we extrapolate from a rodent study that next to every senescent cell in our bodies there is a macrophage? And from that macrophage quercetin is diffusing out of the macrophage and into the senescent cell?
In my mind, that's really, really pushing it. Trying to rationalize this improbable process enough to play devil's advocate is making my head hurt.
ie: Quercetin Glucuronide seems to be converted into Quercetin Aglycone exactly where we want it; the senescent cells with their inflammation and dysfunctional mitochondria!?
And a good thing too as Quercetin Aglycone causes DNA damage. (admittedly at in vivo type dosages)
https://cse.google.c...cone DNA damage
Here you mention that it's a good thing that Quercetin aglycone is converted to to the gluconoride. You say this is a good thing because it causes DNA damage.
Well, I agree with you. It's a good thing we all have livers to do this job. But quercetin gluconoride has not been shown to be active against senescent cells. Nor could it even try to be since the gluconoride part of the molecule is hydrophillic and that does not allow the quercetin gluconoride to diffuse across membranes. This needs to happen since the targets are inside the cell.
I guess what I am getting at is that I am confused. You are happy that it is gluconorated but since that is not the active form I don't understand why since the aglycone is the form we need.
Now as we already have gaunt faces from killing of more than just senescent adipose tissue with 'more is better!' doses of Dasatinib, I think it wise to look very carefully at the differences in bioavailability and pharmacokinetics, of Q, in mice and humans, to work out exactly how much Q to take and how often to take it, before someone dissolves a blood vessel in their brain or something! 
A local search:
http://www.longecity...ndpost&p=722696
continued in
http://www.longecity...ndpost&p=722703
(NB that these links are to a local senolytic thread... and you are actually going to have to click them to understand their context and thus the information they contain!
Clicking the top link, the first thing I see written in bright red:
"After the liver, quercetin exists in the blood solely as quercetin glucuronides. Regardless of initial source, all forms of quercetin undergo hydrolysis and get glucuronidated in the liver before being released into systemic circulation."
Huh. Looks like someone else figured this out already.
There are also some numbers regarding quercetin's bioavailabilty, that look like they support the aglycone being bioavailability. Okay, I'll bite. I click though and I arrive at the following paper:
"Daily Quercetin Supplementation Dose-Dependently Increases Plasma Quercetin Concentrations in Healthy Humans" J. Nutr. September 2008 vol. 138 no. 9 1615-1621
From the above I find the quote:
"In all species investigated so far, including humans, pigs, and rats, quercetin and its methylated derivatives with an intact flavonol structure (isorhamnetin, tamarixetin) are not present as free aglyca but only in the conjugated form (mainly glucuronide and sulfate conjugates)."
Reading lower, I find a table that seems to indicate that quercetin aglycone is available in plasma after dosing. (Table 2)
Uh oh. Am I wrong?
Nope. In the methods section it states that the plasma samples are treated prior to processing:
" All samples were treated enzymatically with β-glucuronidase/sulfatase type H-2 (crude enzyme extract from Helix pomatia; Sigma-Aldrich AG) prior to the extraction of the flavonols."
So what it looks like to me is that there is this company that sells some formulation of quercetin and they found a bunch of articles and misquoted them to support the sale of their product.
Edited by jmorris, 26 April 2017 - 10:27 PM.
