15 replies to this topic

[maxwatt]

There were several press articles recently on drug testing; it seems some men with two copies of a certain gene, do not test positive for testosterone using the standard urine test for testosterone glucuronide. They don't metabolize it that way due to a genotypic variant in the UGT2B17 enzyme. It was a stated that 60% of East Asians have this gene combination, whereas only 10% of Europeans do. This gene combination should result in much higher serum levels for a given dose of resveratrol, as well as for many drugs, including morphine.

The paper “Doping Test Results Dependent on Genotype of UGT2B17, the Major Enzyme for Testosterone Glucuronidation” will appear in the June issue of [Journal of Clinical Endocrinology & Metabolism] JCEM, a publication of The Endocrine Society

Steroid Report
Large Differences in Testosterone Excretion in Korean and Swedish Men Are Strongly Associated with a UDP-Glucuronosyl Transferase 2B17 Polymorphism
http://jcem.endojour...t/full/91/2/687

[Hedgehog]

There were several press articles recently on drug testing; it seems some men with two copies of a certain gene, do not test positive for testosterone using the standard urine test for testosterone glucuronide. They don't metabolize it that way due to a genotypic variant in the UGT2B17 enzyme. It was a stated that 60% of East Asians have this gene combination, whereas only 10% of Europeans do. This gene combination should result in much higher serum levels for a given dose of resveratrol, as well as for many drugs, including morphine.

The paper "Doping Test Results Dependent on Genotype of UGT2B17, the Major Enzyme for Testosterone Glucuronidation" will appear in the June issue of [Journal of Clinical Endocrinology & Metabolism] JCEM, a publication of The Endocrine Society

Steroid Report
Large Differences in Testosterone Excretion in Korean and Swedish Men Are Strongly Associated with a UDP-Glucuronosyl Transferase 2B17 Polymorphism
http://jcem.endojour...t/full/91/2/687

I thought Lance was half asian! This might help explain some of blood plasma results of me vs an Asian friend. Thanks MaxWattage!

[edward]

There are lots of cases of ethnicity and different levels of enzymes. Poor metabolizers Cytochromes P450 http://www.cnsspectr...x?articleid=647 are often whites 5-10% are signifigantly bad metabolizers often requiring half the dose of some drugs.

Here is a study that says that points to more blacks being poor at the n-Glucuronidation of nicotine and continine http://jpet.aspetjou.../291/3/1196.pdf


I still have issues with messing with our natural detoxification systems in order to boost the levels of a certain supplement... seems like one reason there are genetic, often racial, differences is perhaps because different people in different parts of the world were exposed to different toxins, selecting for the upregulating of one enzyme system or another. Again messing with this when we aren't sure all the ramifications seems like a bad idea.

I'm all for delivering Resveratrol to the the walls of the intestinal lumen unmolested but once its in the blood stream I still have issues about shutting down natural defenses in order to let it remain at high blood levels... especially with all the other stuff I am ingesting... This is the whole anti-piperine argument, which I waffle back and forth on.

[edward]

Honestly I think injecting resveratrol IM or SQ might be safer than shutting down multiple enzyme systems, if you really want good blood levels. A bit extreme but you get my point, the risks of shutting down multiple enzyme systems are in my opinion on par to an equally extreme solution of injectable Resveratrol... Now how can we create a sterile injectable form...

Edited by edward, 09 May 2008 - 11:03 PM.

[niner]

There were several press articles recently on drug testing; it seems some men with two copies of a certain gene, do not test positive for testosterone using the standard urine test for testosterone glucuronide. They don't metabolize it that way due to a genotypic variant in the UGT2B17 enzyme. It was a stated that 60% of East Asians have this gene combination, whereas only 10% of Europeans do. This gene combination should result in much higher serum levels for a given dose of resveratrol, as well as for many drugs, including morphine.

The paper “Doping Test Results Dependent on Genotype of UGT2B17, the Major Enzyme for Testosterone Glucuronidation” will appear in the June issue of [Journal of Clinical Endocrinology & Metabolism] JCEM, a publication of The Endocrine Society

Steroid Report
Large Differences in Testosterone Excretion in Korean and Swedish Men Are Strongly Associated with a UDP-Glucuronosyl Transferase 2B17 Polymorphism
http://jcem.endojour...t/full/91/2/687

While UGT2B17 is able to conjugate some xenobiotics , resveratrol is mostly glucuronidated by UGT1A1 and 1A9, so I'm not sure that people who have the deletion polymorphism would see much of a difference in resveratrol metabolism. Also, sulfation is more important (by exactly how much I'm not sure) as a resveratrol conjugation pathway than is glucuronidation. I don't know if these guys actually looked at 2B17, so I certainly couldn't rule it out, but it's probably not a huge effect if any.

J Pharm Pharmacol. 2006 Apr;58(4):469-79.
Glucuronidation of trans-resveratrol by human liver and intestinal microsomes and UGT isoforms.Brill SS, Furimsky AM, Ho MN, Furniss MJ, Li Y, Green AG, Bradford WW, Green CE, Kapetanovic IM, Iyer LV.
Toxicology and Metabolism, Biosciences Division, SRI International, Menlo Park, CA 94025, USA.

Resveratrol (trans-resveratrol, trans-3,5,4'-trihydroxystilbene) is a naturally occurring stilbene analogue found in high concentrations in red wine. There is considerable research interest to determine the therapeutic potential of resveratrol, as it has been shown to have tumour inhibitory and antioxidant properties. This study was performed to investigate the glucuronidation of resveratrol and possible drug interactions via glucuronidation. Two glucuronide conjugates, resveratrol 3-O-glucuronide and resveratrol 4'-O-glucuronide, were formed by human liver and intestinal microsomes. UGT1A1 and UGT1A9 were predominantly responsible for the formation of the 3-O-glucuronide (Km = 149 microM) and 4'-O-glucuronide (Km = 365 microM), respectively. The glucuronide conjugates were formed at higher levels (up to 10-fold) by intestinal rather than liver microsomes. Resveratrol was co-incubated with substrates of UGT1A1 (bilirubin and 7-ethyl-10-hydroxycamptothecin (SN-38)) and UGT1A9 (7-hydroxytrifluoromethyl coumarin (7-HFC)). No major changes were noted in bilirubin glucuronidation in the presence of resveratrol. Resveratrol significantly inhibited the glucuronidation of SN-38 (Ki = 6.2 +/- 2.1 microM) and 7-HFC (Ki = 0.6 +/- 0.2 microM). Hence, resveratrol has the potential to inhibit the glucuronidation of concomitantly administered therapeutic drugs or dietary components that are substrates of UGT1A1 and UGT1A9.

PMID: 16597364

[maxwatt]

Other groups have looked at UGT1A1 polymorphisms:

Anticancer Drugs. 2007 Jul;18(6):693-6. Links
Distribution of the UGT1A1*28 polymorphism in Caucasian and Asian populations in the US: a genomic analysis of 138 healthy individuals.Liu JY, Qu K, Sferruzza AD, Bender RA.
Department of Hematology/Oncology, Quest Diagnostics Nichols Institute, San Juan Capistrano, California 92690, USA.

The hepatic isoform 1A1 of uridine diphosphate glucuronosyltransferase is responsible for glucuronidation and detoxification of SN-38, the active metabolite of irinotecan. The presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter leads to a significant decrease in SN-38 glucuronidation. Patients with the UGT1A1 (TA)7 allele are more likely to experience severe neutropenia and diarrhea following irinotecan chemotherapy. We assessed the distribution of the UGT1A1 (TA)n polymorphism in healthy male and female US residents of European and Asian descent. We used a fluorescent polymerase chain reaction-based assay to detect UGT1A1 (TA)n polymorphisms in 138 healthy volunteers (56 Caucasians, 37 Chinese, 37 Filipino and eight Japanese) between the ages of 18 and 65 years. The chi-test was used to assess between-group differences in the distribution of UGT1A1 (TA)n genotypes. The UGT1A1 (TA)6/6 genotype was significantly more common in Asians than in Caucasians (76 vs. 46%), whereas the (TA)6/7 (39 vs. 20%) and (TA)7/7 (13 vs. 5%) genotypes were more common in Caucasians than in Asians. Genotype distributions did not differ significantly between men and women in either group. The UGT1A1 (TA)5/5 genotype was detected in one Caucasian woman. In conclusion, consistent with previous reports, the UGT1A1 (TA)7/7 genotype was significantly more common in Caucasians than in Asians. UGT1A1 (TA)n/n genotype distribution did not vary with sex in individuals of European or Asian descent.

PMID: 17762398

There is a lot more on the subject HERE

It does seem to show that Asians, as a group, show lower glucuronidation of xenobiotics. This is more important in the intestines, where mostly glucuronidation of resveratrol occurs. Once it's in the blood (and thence to the liver) sulfonation is the primary metabolic consequence. But this particular allele would result in higher serum levels from the same dose, at least initially, before the liver sufonates it. Whether this translates to a better effect or not would require extensive testing.

I know of a group of Chinese taking resveratrol in 500 mg + doses; they report much greater weight loss than do the mostly caucasian imminst members using resveratrol. Not conclusive, I know, but it may be indicative.

Edited for speling

Edited by maxwatt, 10 May 2008 - 02:11 PM.

[krillin]

resveratrol is mostly glucuronidated by UGT1A1 and 1A9

It's also hit by 1A10. Has anyone found any others?

Arch Biochem Biophys. 2001 Sep 15;393(2):281-9.
Regioselective and stereospecific glucuronidation of trans- and cis-resveratrol in human.
Aumont V, Krisa S, Battaglia E, Netter P, Richard T, Mérillon JM, Magdalou J, Sabolovic N.
Groupe d'Etude des Substances Naturelles à Intérêt Thérapeutique (EA 491), Université Victor Segalen Bordeaux 2, Bordeaux, France.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol present in wine, which has been reported to have anti-inflammatory, anti-platelet, and anti-carcinogenic effects. The glucuronidation of this compound and that of the cis-isomer also naturally present, has been investigated in human liver microsomes. Both isomers were actively glucuronidated. The reaction led to the formation of two glucuronides (3-O- and 4'-O-glucuronides), whose structure was characterized by LC-MS and proton NMR. Glucuronidation was regio- and stereoselective. It occurred at a faster rate with the cis-isomer and preferred the 3-position on both isomers. In addition, the glucuronidation of resveratrol was tested using several recombinant UDP-glucuronosyltransferase (UGT) isoforms. The reaction was catalyzed by UGT of the family 1A (UGT1A1, 1A6, 1A7, 1A9, 1A10). The bilirubin conjugating UGT1A1 was mainly involved in the 3-O-glucuronidation of trans-resveratrol, whereas the phenol conjugating UGT1A6 activity was restricted to cis-resveratrol. The UGT1A9 and 1A10 were active toward both isomers. The activity supported by UGT2B7 and UGT2B15 was very low and restricted to cis-resveratrol. UGT1A3, 1A4, 2B4, and 2B11 were unable to form resveratrol glucuronides. Copyright 2001 Academic Press.

PMID: 11556815

[graatch]

Here is a study that says that points to more blacks being poor

often whites 5-10% are signifigantly bad

[maxwatt]

Here is a study that says that points to more blacks being poor

often whites 5-10% are signifigantly bad

Karl Rove?

[Anthony_Loera]

Edited by Anthony_Loera, 21 May 2008 - 03:37 PM.

[edward]

Here is a study that says that points to more blacks being poor

often whites 5-10% are signifigantly bad

lol that is amusing that simply snipping off the last part of both those quotes suddenly becomes amazingly inflammatory

[edward]

whats more amusing is that this will be forever immortalized and indexed by Google, allowing many to read it out of context and if they have the attention span of many people I know (including myself at times) may not even get the joke and conclude that we immortalists are a bunch of racist eugenicists, scary

[edward]

immortalists are a bunch of racist eugenicists

[luminous]

immortalists are a bunch of racist eugenicists

Maybe we can incorporate that facet into the new forum name.

maxwatt--If your hunch is correct--that possibly 60% of East Asians have a heightened sensitivity to resveratrol--then this is important stuff. I wonder if you're the first one to figure it out.

[maxwatt]

immortalists are a bunch of racist eugenicists

Maybe we can incorporate that facet into the new forum name.

maxwatt--If your hunch is correct--that possibly 60% of East Asians have a heightened sensitivity to resveratrol--then this is important stuff. I wonder if you're the first one to figure it out.

I'm the first one to mention it here. But it is known in regard to many medicines, that East Asians require one-tenth the dose of certain medicines than Caucasians. (I think valium is one such, could be wrong.)

[edward]

immortalists are a bunch of racist eugenicists

Maybe we can incorporate that facet into the new forum name.

maxwatt--If your hunch is correct--that possibly 60% of East Asians have a heightened sensitivity to resveratrol--then this is important stuff. I wonder if you're the first one to figure it out.

I'm the first one to mention it here. But it is known in regard to many medicines, that East Asians require one-tenth the dose of certain medicines than Caucasians. (I think valium is one such, could be wrong.)

Interestingly (annectodotal), my wife is East Asian and she does tend to be very sensitive to medicine and supplements, she takes 1/4th the Res Dose I take and still after all this time reports an energy buzz every time she takes it, I only get that now when I up dosages or try different delivery methods (I am caucasian).

Edited by edward, 23 May 2008 - 05:12 PM.