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The Blue Zone Diet In Japan - Is Soy / Tofu Right for YOU? Implications for BPA, Milk Thistle, Andrographis, Tylenol, Benzo's, And Other RX Drugs.

Updated: Feb 27

This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.


In the Series on Netflix, The Blue Zone Series, How To Live To 100, the diet of a particular area of Japan, was studied, that of Okinawa. Their diet, is high in Serine (see prior blog article on Thyroid Nutrition), Purple Potatoes (think binders), and various vegetables, fruits, herbs, and soy / tofu.


Soy and tofu has some controversy around it as soy is one of the 7 most common food allergens (Gluten / Wheat, Dairy, Eggs, Soy, Tree Nuts, Peanuts, and Seafood), as well as estrogenic. I dug in a little bit to try and understand a bit more, and low and behold i was able to connect a couple of things the same gene that process soy, also processes estrogens, BPA / Plastic toxins. There have been a few clients with SKY HIGH BPA levels on toxicity panels, but lived quite clean. All double mutated (homozygous on a key location on UGT2B15 (rs 1902023) - the gene primarily responsible for processing estrogens, androgens, soy, and BPA). BPA also can go through UGT1A1, but mostly through UGT2B15.


So what did i find when i poked around different populations in terms of their propensity for being mutated on this important UGT2B15 location ?


Homozygous variants were over 2X more common in the American population, than in South Asian populations! [20] Hmmm. I dont have specific genetics, on Okinawa, but it has my gears turning for sure. Further, we know that serine is an important amino acid to facilitate thyroid health, and neuro transmitter health (converts to glycine). Serine is also an important amino acid in cellular membrane health - there is a special genetic transporter that takes phosphatidyl serine into the inner membrane of the mitochondria. Phosphatidyl serine is often recommended for people who suffer traumatic brain injuries, and can lower cortisol too. And finally, Soy / Tofu has an amino acid profile that is extremely skewed to Tryptophan, Tyrosine, and Phenylalinene - much more so than animal proteins - and these amino acids are the same ones used in pathways to make dopamine and serotonin! Perhaps, this is one contributing factor to lower rates of dementia, and Parkinson's in these populations.


The Bottom Line:

If you are genetically compromised on this gene - soy, tofu, acetominophen, benzo's, estrogenic compounds, and rx products may stress this pathway. And if you are considering having children, just know they cannot detox BPA early on in their development in the fetus. Lastly, both milk thistle and andrographis may not be right for you. For women, there are literally dozens of articles that link this gene, and specific mutations to breast cancer, for obvious reasons; and we wonder why BPA is linked as well.


UGT2B15: Processes Acetominophen, BPA, Soy, Certain Pharmaceuticals and Benzo's

"UDP-glucuronosyltransferase 2B15 (UGT2B15) is a crucial phase II drug-metabolizing enzyme, which glucuronidates various compounds, including clinical drugs and hormones. Mutants might affect glucuronidation, leading to a disruption of drug metabolism in vivo and decrease of therapeutic effect. Here, we mainly analyzed two representative mutants, H401P and L446S, on UGT2B15 activity using glucuronidation assays, molecular dynamic (MD) simulation and X-ray diffraction methods. The enzyme activity of L446S obviously increased six-fold than the wild type, although the enzyme activities of P191L, T374A, and H401P were lost apparently. Furthermore, we used MD simulations to calculate the energy change in the catalytic process of H401P and L446S, and the results indicated the free binding energies of H401P mutant to oxazepam and UDPGA were −30.98 ± 1.00 kcal/mol and −36.42 ± 1.04 kcal/mol, respectively, increased obviously compared to wild type, suggesting the mutation on position 401 had a crucial effect on the catalysis."[23].


Genetic variation may result in intermediate metabolizer (IM) status and subsequent increased serum levels of some benzodiazepines.[19]. Chlordiazepoxide, Clorazepate, Clorazepate, Diasepam, Lorazepam, Oxazepam are all process by UGT2B15 too [19], along with Eltrombopag, Trofinetide, [21].


UGT2B15 important to clear acetominophen and soy [24].


"Bisphenol A (BPA) is one of a number of potential endocrine-disrupting chemicals, which are metabolized mainly by UDP-glucuronosyltransferase 2B15 (UGT2B15) in humans. Six UGT2B15 allelic variants (UGT2B15*2, UGT2B15*3, UGT2B15*4, UGT2B15*5, UGT2B15*6, and UGT2B15*7; wild-type, UGT2B15*1) with amino acid substitutions have been found in Caucasian, African-American, Hispanic, and Oriental populations to date. In this study, the effects of amino acid substitutions in UGT2B15 on BPA glucuronidation were studied using recombinant UGT2B15 enzymes of wild-type (UGT2B15.1) and all identified variants (UGT2B15.2, UGT2B15.3, UGT2B15.4, UGT2B15.5, UGT2B15.6, and UGT2B15.7) expressed in insect (Sf9) cells. The K (m), V (max), and CL (int) values of UGT2B15.1 for BPA glucuronidation were 3.9 μM, 650 pmol/min/mg protein, and 170 μL/min/mg protein, respectively. Although there is no significant difference in the K (m) value between wild-type and any variant UGT2B15, the V (max) and CL (int) values of UGT2B15 variants having D85Y substitution were markedly reduced to 14 and 10% for UGT2B15.2, and 4.3 and 3.9% for UGT2B15.5 compared with those of UGT2B15.1, respectively. However, the K (m), V (max), and CL (int) values of UGT2B15.3, UGT2B15.4, UGT2B15.6, and UGT2B15.7 having L86S, T352I, and/or K523T substitution(s) for BPA glucuronidation were comparable to those of UGT2B15.1. These findings suggest that D85Y substitution in UGT2B15 decreases enzymatic function and that the polymorphic alleles of UGT2B15 are closely associated with variations in the metabolism and toxicity of BPA. The information gained in this study should help with in vivo extrapolation to assess the toxicity of endocrine-disrupting chemicals."[25]


Developing Fetus's May Be Unable To Clear BPA - Frightening If Mother Is Toxic

Further, one research article in particular [102] shows that certain UGT enzymes do not develop in young children and the fetus until later on, which would leave them unable to metabolize some of the toxins like BPA while they are in certain developmental phases in the mothers womb. Holy cow! This means, that normal BPA exposure to the unborn fetus early on could harm the health of these developing children because they have no capacity to clear these toxins. This feels important to communicate to females considering children - detox your BPA, and plastics, and measure your body burden if you can prior to getting pregnant so you do not expose your children in your womb.


Milk Thistle and Andrographis are Potent Inhibitors of UGT2B15

A variety of herbs have been shown to inhibit various glucuronidation genes, and specifically for this gene, UGT2B15, milk thistle, and andrographis (aka ParActin) are the culprits. Inhibition of more common UGT (Glucuronidation) Enzymes [26,27]:


UGT1A1: Milk Thistle, Cranberry, Echinacea, Grape Seed, Hawthorne , Milk Thistle, Genistein (Soy), St Johns Wort, Valerian, Andrographis


UGT1A6: Milk Thistle, Andrographis


UGT1A9: St Johns Wort, Hawthorne, Milk Thistle, Grape Seed, Gingko, Cranberry,


UGT2B7: Valerian, Milk Thistle


UGT2B15: Milk Thistle, Andrographis


At low concentrations of BPA, 80% goes through UGT2B15, at higher concentrations, UGT1A9 is brought into the mix, and processes 50% of BPA. "Relative activity factor normalization indicated that UGT2B15 contributes >80% of activity at bisphenol-A concentrations under 5 μM, while UGT1A9 contributes up to 50% of activity at higher concentrations." [29]


The BPA that is not glucuronidated through UGT2B15, UGT1A1, or UGT1A9, gets sulfated through SULT1A1. [30] If all of these genes are compromised, its a situation that should be monitored closely through testing and exposure minimization.


What is UGT2B15? [1,2,3,7]

The UGT2B15 enzyme is Phase II detox gene highly expressed in the liver and mediates the metabolism of a wide range of substrates, including therapeutic medications such as benzodiazepines.

UGT2B15*2 is associated with decreased glucuronidation and has been shown to be a significant determinant of interindividual variability in the clearance of oxazepam and lorazepam.


UGT2B15 : Mutations Can Reduce The Metabolism Of Benzodiazepines[1,2,7,9,10,11,12]

2 of 5 studies found a strong effect of UGT2B15 on oxazepam metabolism. The UGT2B15*2 variant has also been shown to affect the metabolism of lorazepam. One in vivo study found that homozygous carriers of the UGT2B15*2 variant exhibited a 40-50% lower metabolic activity and systemic clearance of lorazepam compared to wild-type.


Valproic Acid Also Inhibits UGT2B15 [1,2,3,7,9,12,13,14,15,17, 18]

Multiple studies have shown that UGT2B15*2 mutations ares associated with lower enzyme activity, which could result in elevated plasma concentrations and reduced clearance of drugs that are substrates of UGT2B15. Valproic acid has been shown to inhibit glucuronidation of UGT2B15 substrates. Studies have shown that coadministration of lorazepam and valproic acid reduces the clearance of lorazepam. This drug-drug interaction may be clinically significant since it could potentially lead to drug toxicity. The FDA recommends that the dosage of lorazepam should be reduced by approximately 50% when co-administered with valproic acid coincidentally.


References:

1. He, X. et al. Evidence for oxazepam as an in vivo probe of UGT2B15: Oxazepam clearance is reduced by UGT2B15 D85Y polymorphism but unaffected by UGT2B17 deletion. Br. J. Clin. Pharmacol. 68, 721–730 (2009).

2. Court, M. H. et al. UDP-glucuronosyltransferase (UGT) 2B15 pharmacogenetics: UGT2B15 D85Y genotype and gender are major determinants of oxazepam glucuronidation by human liver. J. Pharmacol. Exp. Ther. 310, 656–665 (2004).

3. Uchaipichat, V., Suthisisang, C. & Miners, J. O. The glucuronidation of R- and S-lorazepam: Human liver microsomal kinetics, UDPglucuronosyltransferase enzyme selectivity, and inhibition by drugs. Drug Metab. Dispos. 41, 1273–1284 (2013).

4. Levesque, E., Beaulieu, M., Green, M.D., Tephly, T.R., Belanger, A., Hum, D. W. Isolation and characterization of UGT2B15(Y85): a UDPglucuronosyltransferase encoded by a polymorphic gene. Pharmacogenetics 7, 317–325 (1997).

5. Riedy, M. et al. Genomic organization of the UGT2b gene cluster on human chromosome 4q13. Pharmacogenetics 10, 251–60 (2000).

6. Hwang, M. et al. Genetic Variations in UDP-glucuronosyltransferase 2B7 Gene ( UGT2B7 ) in a Korean Population. Drug Metab. Pharmacokinet. 25, 398–402 (2010).

7. Chung, J. Y. et al. Effect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers. Clin. Pharmacol. Ther. 77, 486–494 (2005).

8. Lampe, J. W., Bigler, J., Bush, A. C., E, U. F. U. D. & Potter, J. D. Prevalence of Polymorphisms in the Human UDP-Glucuronosyltransferase 2B Family : UGT2B4 ( D 458 E ) , UGT2B7 ( H 268 Y ) , and UGT2B15 ( D 85 Y ) Prevalence of Polymorphisms in the Human. Cancer Epidemiol. Biomarkers Prev. 4, 329–333 (2000).

9. Court, M. H. et al. Stereoselective Conjugation of Oxazepam By Human Udp- Glucuronosyltransferases ( Ugts ): S -Oxazepam Is Glucuronidated By Ugt2B15 , While R -Oxazepam Is Glucuronidated By Ugt2B7 and Ugt1a9 Abstract : 30, 1257–1265 (2002).

10. Liu, W. et al. Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver. Hum. Mol. Genet. 23, 5558–69 (2014).

11. Nishihara, M., Hiura, Y., Kawaguchi, N., Takahashi, J. & Asahi, S. UDP-glucuronosyltransferase 2B15 (UGT2B15) Is the Major Enzyme Responsible for Sipoglitazar Glucuronidation in Humans: Retrospective Identification of the UGT Isoform by In Vitro Analysis and the Effect of UGT2B15*2 Mutation. Drug Metab. Pharmacokinet. 28, 475–484 (2013).

12. Court, M. H. Isoform-selective probe substrates for in vitro studies of human UDP-glucuronosyltransferases. Methods Enzymol. 400, 104–116 (2005).

13. Ethell, B. T., Anderson, G. D. & Burchell, B. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDPglucuronosyltransferases. 65, 1441–1449 (2003).

14. Chung, J.-Y. et al. Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin. Pharmacol. Ther. 83, 595–600 (2008).

15. Samara, E. E., Granneman, R. G., Witt, G. F. & Cavanaugh, J. H. Effect of valproate on the pharmacokinetics and pharmacodynamics of lorazepam. J. Clin. Pharmacol. 37, 442–450 (1997).

16. Anderson, G.D., Gidal, B.E., Kantor, E.D., Wilensky, A. J. Lorazepam-Valproate Interaction: Studies in Normal Subjects and Isolated Perfused Rat Liver. Epilepsia 35, 221–225 (1994).

17. Lee, S.-A., Lee, J. K. & Heo, K. Coma probably induced by lorazepam-valproate interaction. Seizure 11, 124–5 (2002).

18. FDA Label. Ativan (lorazepam) tablets. (2007).

19. Genomind

20. GenomeAdBrowser

22. Human Hepatic UGT2B15 Developmental Expression. By Karthika Divakaran,1 Ronald N. Hines,2 and D Gail McCarver. Toxicol Sci. 2014 Sep 1; 141(1): 292–299. Published online 2014 Sep 12. doi: 10.1093/toxsci/kfu126. PMCID: PMC4271124. PMID: 24980262

23. The structural basis of conserved residue variant effect on enzyme activity of UGT2B15. Lin Zhang, Xuerong Zhang, et. al. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. Volume 1871, Issue 3, 1 May 2023, 140888. https://doi.org/10.1016/j.bbapap.2023.140888

24. UGT1A6 and UGT2B15 Polymorphisms and Acetaminophen Conjugation in Response to a Randomized, Controlled Diet of Select Fruits and Vegetables. By Sandi L. Navarro, Yu Chen, et. al. Drug Metab Dispos. 2011 Sep; 39(9): 1650–1657. doi: 10.1124/dmd.111.039149. PMCID: PMC3164274. PMID: 21666065

25. Effect of UDP-glucuronosyltransferase 2B15 polymorphism on bisphenol A glucuronidation

Nobumitsu Hanioka 1Hiroyuki Oka, et. al. Arch Toxicology. . 2011 Nov;85(11):1373-81.

doi: 10.1007/s00204-011-0690-5. Epub 2011 Mar 15. PMID: 21404072. DOI: 10.1007/s00204-011-0690-5

26. Effects of Herbal Supplements on Drug Glucuronidation. Review of Clinical, Animal, and In Vitro Studies. Authors Mohamed-Eslam F. Mohamed, Reginald F. Frye. DOI http://dx.doi.org/ 10.1055/s-0030-1250457 Published online November 3, 2010 Planta Med 2011; 77: 311–321 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0032‑0943.

27. Effects of Andrographis paniculata and Orthosiphon stamineus Extracts on the Glucuronidation of 4-Methylumbelliferone in Human UGT Isoforms. Sabariah Ismail,1,* Nur Aziah Hanapi. Molecules. 2010 May; 15(5): 3578–3592. Published online 2010 May 14. doi: 10.3390/molecules15053578. PMCID: PMC6263374. PMID: 20657500

28. 1. UGT2B15 UDP glucuronosyltransferase family 2 member B15 [ Homo sapiens (human) ]. NIH: Gene ID: 7366, updated on 23-Nov-2023

29. Bisphenol-A glucuronidation in human liver and breast: identification of UDP-glucuronosyltransferases (UGTs) and influence of genetic polymorphisms

Christina M Street 1Zhaohui Zhu, et. al. Xenobiotica. 2017 Jan;47(1):1-10.

doi: 10.3109/00498254.2016.1156784. Epub 2016 Mar 21. PMID: 26999266

30. Bisphenol A sulfonation is impaired in metabolic and liver disease. By Emine B. Yalcin,* Supriya R. Kulkarni. Toxicol Appl Pharmacol. Author manuscript; available in PMC 2017 Feb 1. Toxicol Appl Pharmacol. 2016 Feb 1; 292: 75–84. Published online 2015 Dec 19. doi: 10.1016/j.taap.2015.12.009. PMCID: PMC4724572. NIHMSID: NIHMS751414

PMID: 26712468




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