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Glucarate estrogen blocker?

pattismith

Senior Member
Messages
3,926
the idea that Glucarate favors estrogen blocking is widely spread on the net, but after reading available scientific papers abstracts, I am not convinced at all.

It is believed that Glucarate and its metabolite glucaro1.4 lactone are glucuronidase inhibitors (reverse the UDP-GT glucuronidation) and that glucarate is a UDP-Glucuronyl Transferase activator (this kind of enzyme binds hormones for subsequent elimination)….

My personal small experiment with glucarate produced warm feeling and breast pressure, so it doesn't completely fit with estrogen blocking.

In selfhacked it is only quoted as a possible glucuronidase inhibitor (but not as an UDP-GT activator), and this recent study shows that in fact glucarate could be an inhibitor of some UDP-GT:

Inhibitory Effects of Endogenous Linoleic Acid and Glutaric Acid on the Renal Glucuronidation of Berberrubine in Mice and on Recombinant Human UGT1A7, 1A8, and 1A9.
Yang N1, Li S1, Yan C1, Sun R1, He J1, Xie Y1, Peng Y1, Wang G2, Aa J2.
2018

Abstract

Berberrubine (BRB) has a strong lipid-lowering effect and can be extensively metabolized into berberrubine-9-O-β-d-glucuronide (BRBG) in vivo.

Recently, pharmacokinetics studies showed that the production of BRBG was significantly decreased in the urine of mice fed with a high-fat diet (HFD), indicating a decreased glucuronidation capacity.

Based on the UDP-glucuronosyltransferase (UGT) isoform identification, hepatic and renal microsomal incubation, glucuronidation was examined to suggest the metabolism of BRB in liver and kidneys.

The results showed that the renal UGT activity for metabolizing BRB markedly decreased, which may be highly related to the decreased expression and activity of renal Ugt1a7c.

Surprisingly, in vitro studies revealed neither BRB nor BRBG inhibited the renal UGT activity.

By employing an integrated strategy of metabolomics and pharmacokinetics, we identified and confirmed for the first time the inhibitory effect of some potential endogenous molecules on the renal glucuronidation of C57BL/6J mice, such as glutaric acid (GA) and linoleic acid (LA).

By employing recombinant human UGTs, we found that GA and LA efficiently affect the activity of recombinant human UGT1A7, 1A9, and 1A8 at their normal or abnormal physiologic levels in vivo.

GA (2 mM) markedly inhibited the activity of UGT1A7 by 89.4% and UGT1A9 by 32.8%.
The inhibition rates reached 99.3% for UGT1A9, 48.3% for UGT1A7, and 46.8% for UGT1A8 with LA at 200 μM.
It has been suggested that the endogenous molecules have the potential to affect the efficiency of glucuronidation, which might be a key factor contributing to individual differences in drug metabolism.
 
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pattismith

Senior Member
Messages
3,926
This recent paper even states that saccharolactone (= Glucaro1.4 lactone) is not the glucuronidase inhibitor that the scientific community once thought!


Curr Drug Metab. 2018;19(4):304-309. doi: 10.2174/1389200219666171229232007.
Saccharolactone: The History, the Myth, and the Practice.
Argikar UA1.


Abstract
BACKGROUND:
Over the past two decades, saccharolactone has been routinely used in in vitro microsomal incubations, and sometimes in incubations with recombinant Uridine diphosphoglucuronosyl transferases (UGT) while investigating glucuronidation reactions. The addition of saccharolactone is aimed at completely inhibiting β-glucuronidases that may be present in the microsomes, in the anticipation of accurate identification and quantification of the formed glucuronide metabolites. Recent research has demonstrated that saccharolatone may not serve the intended objective, and may even lead to inhibition of certain UGTs.

OBJECTIVE:
This report investigates the historic evidence in the practice of saccharolactone addition in relation to β- glucuronidases and UGTs. The chemical nature and inhibition potency of saccharolactone are explored in an attempt to unravel the myth in its application. Finally, the collective evidence is discussed in an effort to provide guidance to drug metabolism scientists on the utilization of saccharolactone.

CONCLUSION:
In-depth evaluation of the experimental evidence in the literature points toward a weak rationale for general in vitro application of saccharolactone.
Furthermore, inhibition of recombinant or microsomal UGTs by saccharolactone may be model dependent.


Overall, the integrated data suggests that saccharolactone should not be utilized in in vitro microsomal incubations with the objective of inhibiting β-glucuronidases.
 
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