The UGT family of enzymes is responsible for an important part of phase II detoxification. In this article, I’ll explain what the UGT enzymes do in the body, how your genes impact this part of detoxification, and lifestyle factors that can increase or decrease this detox process.
Brief background: When foreign substances enter the body, such as pollutants or prescription medications, the body breaks the substances down and eliminates them. This whole process is referred to as phase I and phase II detoxification. Phase I detoxification uses the CYP enzymes to oxidize the toxic substance. Then in phase II, the toxic substance is altered again to make it water-soluble. This allows your body to easily excrete the substance.
Related article: Detoxification: Phase I and Phase II Metabolism
What are UGT Enzymes?
The UDP-glucuronosyltransferase (abbreviated UGT) enzymes facilitate a glucuronidation reaction. This term means that one of the UGT enzymes helps make a substance more water-soluble for excretion through urine or feces.
This is important because the phase I detoxification intermediates often cause oxidative stress or other problems in the body. You don’t want them hanging around, damaging cells or DNA. Thus, this phase II process needs to act in sync with phase I, making the substance water-soluble so that it can be quickly eliminated.
What is affected by glucuronidation?
Glucuronidation reactions are used by the body to inactivate and eliminate:
- bilirubin (from the breakdown of old red blood cells)
- retinoids (vitamin A components)
- estrogens and testosterone[ref ]
- BPA and BPS[ref ][ref ]
- certain fatty acids (DHA, oleic acid, linoleic acid)[ref ]
- a lot of medications[ref ], including acetaminophen (Tylenol)[ref ]
- certain pesticides[ref ]
- polycyclic aromatic hydrocarbons (PAHs – carcinogenic)[ref ]
There are many different genetic variants in the UGT family of enzymes. Thus, some people may be more sensitive to certain medications or have a harder time breaking down and eliminating substances such as BPA.
UGT Genetic Variants:
The UGT family of genes codes for the enzymes needed for glucuronidation. Variants in these genes are fairly common, and the variants can increase or decrease the body’s ability to detoxify substances through glucuronidation.
UGT1A1 involves the breakdown of bilirubin, estrogen, and several carcinogens. The body naturally creates bilirubin as it clears out aged red blood cells. The UGT1A1 enzyme is responsible for the final step in making bilirubin easy for the body to get rid of. It is excreted in bile and urine (it’s what makes your poop brown).
Gilbert’s Syndrome is associated with this gene and involves bilirubin not being broken down appropriately. This syndrome leads to periodical increases in the level of unconjugated bilirubin, especially in times of physical stress such as illness, intense exercise, or fasting. This is a fairly common disorder with symptoms that include periodic yellowing of the eyes, abdominal pain, and fatigue.
A common variant, known as UGT1A1*28, has associations with higher bilirubin levels in Caucasian and African populations. There are questions/discrepancies surrounding the validity of the data on this in older 23andMe versions, and the data is not found in newer 23andMe or AncestryDNA versions. If you have data from another source, look for rs3064744.
Check your genetic data for rs4148323 (23andMe v4, v5; AncestryDNA):
- A/A: UGT1A1*6 – increased bilirubin level, Gilbert’s syndrome (in Asian and Indian populations)[ref ][ref ], possibly decreased estrogen metabolism[ref ] may alter dosing for irinotecan (cancer drug)[ref ]
- A/G: Carrier of UG/T1A1*6 (somewhat reduced enzyme activity)
- G/G: typical
Members: Your genotype for rs4148323 is —.
Check your genetic data for rs4124874 (23andMe v4, v5; AncestryDNA):
- G/G: UGT1A1*60[ref] reduced enzyme activity, increased bilirubin (Caucasian populations)[ref ][ref ]
- G/T: one copy of UGT1A1*60
- T/T: typical
Members: Your genotype for rs4124874 is —.
Check your genetic data for rs6742078 (23andMe v4, v5; AncestryDNA):
- T/T: reduced UGT1A1 activity, increased gallstone risk (males)[ref ] increased bilirubin[ref ]
- G/T: somewhat reduced activity
- G/G: typical
Members: Your genotype for rs6742078 is —.
Check your genetic data for rs8330 (23andMe v5; AncestryDNA):
- C/C: typical
- C/G: intermediate UGT1A1 activity
- G/G: slower UGT1A1 activity[ref ]
Members: Your genotype for rs8330 is —.
Check your genetic data for rs35003977 (23andMe v4; AncestryDNA):
- T/T: typical
- G/T: higher bilirubin, Gilbert’s syndrome possible
- G/G: high bilirubin and possible Gilbert’s syndrome[ref ]
Members: Your genotype for rs35003977 is —.
UGT1A6 also helps with transforming bilirubin, hormones, and certain drugs (aspirin, acetaminophen) into water-soluble metabolites for excretion. Studies on this gene also look at the variants in association with benzene poisoning.
Check your genetic data for rs17863783 (23andMev4, v5; AncestryDNA):
- T/T: increased UGT1A6, protective against bladder cancer[ref ]
- G/T: increased UGT1A6
- G/G: typical
Members: Your genotype for rs17863783 is —.
Check your genetic data for rs6714486 (23andMe v4 only)
Members: Your genotype for rs6714486 is —.
If your genetic data shows that you have slower than normal UGT activity, you may want to look into the following:
Can you speed up UGT enzymes?
Cruciferous vegetables cause your body to increase the production of UGT1A1. Cruciferous veggies include broccoli, kale, Brussels sprouts, cauliflower, and cabbage.
If you aren’t eating enough cruciferous veggies, supplements of I3C and DIM (diindolylmethane) are available. They are produced from the part of the cruciferous veggies that induce UGT1A1.[ref ]
Quercetin (flavonoid supplement) and curcumin (from turmeric) both increase UGT enzyme activity, according to an animal study.[ref ]
Avoid toxicants that utilize the UGT enzymes:
- UGT1A1 is also responsible for the breakdown of BPA (in plastics) and BPF. Avoiding these substances may be more important if you carry a slow UGT variant.
- The chemicals perfluorooctanoate (PFOA) and perfluoro octane sulfonate(PFOS) inhibit UGT1A1.[ref ]
How is the gut microbiome connected to phase II detoxification?
Certain gut bacteria produce an enzyme called β-glucuronidase.[ref ][ref ][ref] This enzyme basically reverses the glucuronidation reactions that the UGT enzymes caused. Thus, when the toxic substances that were glucuronidated in phase II detoxification reach the intestines, the process can be reversed by β-glucuronidase. This allows the body to reabsorb the toxic substance again via the intestines. Generally, not a good thing.
A recent study looked at the effect of β-glucuronidase from increasing the number of fruits and vegetables in the diet. The study found that higher fruit and vegetable intake increased β-glucuronidase activity.[ref ]
Calcium d-glucarate is often promoted as a supplement for decreasing β-glucuronidase. I had a really hard time finding studies that show this, other than an animal study from 1990 using a diet with 4% calcium glucarate.[ref ]
The right probiotic strains may reduce β-glucuronidase activity. An animal study showed that fermented milk with several lactobacillus strains reduced β-glucuronidase.[ref ]
Related Articles and Genes:
How your genes influence BPA detoxification:
BPA, a chemical found in some plastics, has been linked to a variety of effects on people including obesity, insulin resistance, and epigenetic effects on the fetus. Genetics plays a role in how quickly you can eliminate BPA from your body.
Nrf2 Pathway: Increasing the body’s ability to get rid of toxins
The Nrf2 (Nuclear factor erythroid 2–related factor) signaling pathway regulates the expression of antioxidants and phase II detoxification enzymes. This is a fundamental pathway that is important in how well your body functions. Your genetic variants impact how well this pathway functions.
Phase I and Phase II detoxification
Learn how the different genetic variants in phase I and phase II detoxification genes impact the way that you react to medications and break down different toxins.
Lithium Orotate + B12: The bee’s knees, for some people…
For some people, low-dose, supplemental lithium orotate is a game-changer when combined with vitamin B12. But other people may have little to no response. The difference may be in your genes.
Bale, Govardhan, et al. “Incidence and Risk of Gallstone Disease in Gilbert’s Syndrome Patients in Indian Population.” Journal of Clinical and Experimental Hepatology, vol. 8, no. 4, Dec. 2018, pp. 362–66. PubMed Central, https://doi.org/10.1016/j.jceh.2017.12.006.
Buch, Stephan, et al. “Loci from a Genome-Wide Analysis of Bilirubin Levels Are Associated with Gallstone Risk and Composition.” Gastroenterology, vol. 139, no. 6, Dec. 2010, pp. 1942-1951.e2. PubMed, https://doi.org/10.1053/j.gastro.2010.09.003.
—. “Loci from a Genome-Wide Analysis of Bilirubin Levels Are Associated with Gallstone Risk and Composition.” Gastroenterology, vol. 139, no. 6, Dec. 2010, pp. 1942-1951.e2. PubMed, https://doi.org/10.1053/j.gastro.2010.09.003.
Court, Michael H., et al. “The UDP-Glucuronosyltransferase (UGT) 1A Polymorphism c.2042C>G (Rs8330) Is Associated with Increased Human Liver Acetaminophen Glucuronidation, Increased UGT1A Exon 5a/5b Splice Variant MRNA Ratio, and Decreased Risk of Unintentional Acetaminophen-Induced Acute Liver Failure.” The Journal of Pharmacology and Experimental Therapeutics, vol. 345, no. 2, May 2013, pp. 297–307. PubMed Central, https://doi.org/10.1124/jpet.112.202010.
Desrouillères, Kerlynn, et al. “Cancer Preventive Effect of a Specific Probiotic Fermented Milk Components and Cell Walls Extracted from a Biomass Containing L. Acidophilus CL1285, L. Casei LBC80R, and L. Rhamnosus CLR2 on Male F344 Rats Treated with 1,2-Dimethylhydrazine.” Journal of Functional Foods, vol. 26, Oct. 2016, pp. 373–84. ScienceDirect, https://doi.org/10.1016/j.jff.2016.08.005.
Dwivedi, Chandradhar, et al. “Effect of Calcium Glucarate on β-Glucuronidase Activity and Glucarate Content of Certain Vegetables and Fruits.” Biochemical Medicine and Metabolic Biology, vol. 43, no. 2, Apr. 1990, pp. 83–92. ScienceDirect, https://doi.org/10.1016/0885-4505(90)90012-P.
Franco, Marco E., et al. “Altered Expression and Activity of Phase I and II Biotransformation Enzymes in Human Liver Cells by Perfluorooctanoate (PFOA) and Perfluorooctane Sulfonate (PFOS).” Toxicology, vol. 430, Jan. 2020, p. 152339. PubMed, https://doi.org/10.1016/j.tox.2019.152339.
Gilbert Syndrome: MedlinePlus Genetics. https://medlineplus.gov/genetics/condition/gilbert-syndrome/. Accessed 20 Sept. 2021.
Girard, Hugo, et al. “The Novel Ugt1a9 Intronic I399 Polymorphism Appears as a Predictor of 7-Ethyl-10-Hydroxycamptothecin Glucuronidation Levels in the Liver.” Drug Metabolism and Disposition, vol. 34, no. 7, July 2006, pp. 1220–28. dmd.aspetjournals.org, https://doi.org/10.1124/dmd.106.009787.
Gramec Skledar, Darja, et al. “Differences in the Glucuronidation of Bisphenols F and S between Two Homologous Human UGT Enzymes, 1A9 and 1A10.” Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 45, no. 6, 2015, pp. 511–19. PubMed, https://doi.org/10.3109/00498254.2014.999140.
Hodgson, Ernest. “Chapter 4 – Introduction to Biotransformation (Metabolism).” Pesticide Biotransformation and Disposition, edited by Ernest Hodgson, Academic Press, 2012, pp. 53–72. ScienceDirect, https://doi.org/10.1016/B978-0-12-385481-0.00004-6.
Kawee-Ai, Arthitaya, and Sang Moo Kim. “Application of Microalgal Fucoxanthin for the Reduction of Colon Cancer Risk: Inhibitory Activity of Fucoxanthin against Beta-Glucuronidase and DLD-1 Cancer Cells.” Natural Product Communications, vol. 9, no. 7, July 2014, pp. 921–24.
Konaka, Ken, et al. “Study on the Optimal Dose of Irinotecan for Patients with Heterozygous Uridine Diphosphate-Glucuronosyltransferase 1A1 (UGT1A1).” Biological & Pharmaceutical Bulletin, vol. 42, no. 11, 2019, pp. 1839–45. PubMed, https://doi.org/10.1248/bpb.b19-00357.
Kuo, Sung-Hsin, et al. “Polymorphisms of ESR1, UGT1A1, HCN1, MAP3K1 and CYP2B6 Are Associated with the Prognosis of Hormone Receptor-Positive Early Breast Cancer.” Oncotarget, vol. 8, no. 13, Mar. 2017, pp. 20925–38. PubMed, https://doi.org/10.18632/oncotarget.14995.
Kuypers, Dirk R. J., et al. “The Impact of Uridine Diphosphate–Glucuronosyltransferase 1A9 (UGT1A9) Gene Promoter Region Single-Nucleotide Polymorphisms T—275A and C—2152T on Early Mycophenolic Acid Dose-Interval Exposure in de Novo Renal Allograft Recipients.” Clinical Pharmacology & Therapeutics, vol. 78, no. 4, 2005, pp. 351–61. Wiley Online Library, https://doi.org/10.1016/j.clpt.2005.06.007.
Maekawa, Shinya, et al. “Association between Alanine Aminotransferase Elevation and UGT1A1*6 Polymorphisms in Daclatasvir and Asunaprevir Combination Therapy for Chronic Hepatitis C.” Journal of Gastroenterology, vol. 53, no. 6, June 2018, pp. 780–86. PubMed, https://doi.org/10.1007/s00535-017-1405-3.
Maruti, Sonia S., et al. “Serum β-Glucuronidase Activity in Response to Fruit and Vegetable Supplementation: A Controlled Feeding Study.” Cancer Epidemiology, Biomarkers & Prevention : A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology, vol. 17, no. 7, July 2008, pp. 1808–12. PubMed Central, https://doi.org/10.1158/1055-9965.EPI-07-2660.
Mehboob, Huma, et al. “Effect of UDP-Glucuronosyltransferase (UGT) 1A Polymorphism (Rs8330 and Rs10929303) on Glucuronidation Status of Acetaminophen.” Dose-Response, vol. 15, no. 3, Sept. 2017, p. 1559325817723731. PubMed Central, https://doi.org/10.1177/1559325817723731.
Oussalah, Abderrahim, et al. “Exome-Wide Association Study Identifies New Low-Frequency and Rare UGT1A1 Coding Variants and UGT1A6 Coding Variants Influencing Serum Bilirubin in Elderly Subjects.” Medicine, vol. 94, no. 22, June 2015, p. e925. PubMed Central, https://doi.org/10.1097/MD.0000000000000925.
—. “Exome-Wide Association Study Identifies New Low-Frequency and Rare UGT1A1 Coding Variants and UGT1A6 Coding Variants Influencing Serum Bilirubin in Elderly Subjects: A Strobe Compliant Article.” Medicine, vol. 94, no. 22, June 2015, p. e925. PubMed, https://doi.org/10.1097/MD.0000000000000925.
Pollet, Rebecca M., et al. “An Atlas of β-Glucuronidases in the Human Intestinal Microbiome.” Structure (London, England : 1993), vol. 25, no. 7, July 2017, pp. 967-977.e5. PubMed Central, https://doi.org/10.1016/j.str.2017.05.003.
Rs4124874 – SNPedia. https://snpedia.com/index.php/Rs4124874. Accessed 20 Sept. 2021.
Russell, W. M., and T. R. Klaenhammer. “Identification and Cloning of GusA, Encoding a New β-Glucuronidase from Lactobacillus Gasseri ADH.” Applied and Environmental Microbiology, vol. 67, no. 3, Mar. 2001, pp. 1253–61. PubMed Central, https://doi.org/10.1128/AEM.67.3.1253-1261.2001.
Shibuya, Ayako, et al. “Impact of Fatty Acids on Human UDP-Glucuronosyltransferase 1A1 Activity and Its Expression in Neonatal Hyperbilirubinemia.” Scientific Reports, vol. 3, Oct. 2013, p. 2903. PubMed, https://doi.org/10.1038/srep02903.
Sten, Taina, et al. “UDP-Glucuronosyltransferases (UGTs) 2B7 and UGT2B17 Display Converse Specificity in Testosterone and Epitestosterone Glucuronidation, Whereas UGT2A1 Conjugates Both Androgens Similarly.” Drug Metabolism and Disposition: The Biological Fate of Chemicals, vol. 37, no. 2, Feb. 2009, pp. 417–23. PubMed, https://doi.org/10.1124/dmd.108.024844.
Tang, Wei, et al. “Mapping of the UGT1A Locus Identifies an Uncommon Coding Variant That Affects MRNA Expression and Protects from Bladder Cancer.” Human Molecular Genetics, vol. 21, no. 8, Apr. 2012, pp. 1918–30. PubMed Central, https://doi.org/10.1093/hmg/ddr619.
TSUNEDOMI, RYOUICHI, et al. “A Novel System for Predicting the Toxicity of Irinotecan Based on Statistical Pattern Recognition with UGT1A Genotypes.” International Journal of Oncology, vol. 45, no. 4, July 2014, pp. 1381–90. PubMed Central, https://doi.org/10.3892/ijo.2014.2556.
van der Logt, E. M. J., et al. “Induction of Rat Hepatic and Intestinal UDP-Glucuronosyltransferases by Naturally Occurring Dietary Anticarcinogens.” Carcinogenesis, vol. 24, no. 10, Oct. 2003, pp. 1651–56. Silverchair, https://doi.org/10.1093/carcin/bgg117.
Vergara, Ana G., et al. “UDP-Glycosyltransferase 3A Metabolism of Polycyclic Aromatic Hydrocarbons: Potential Importance in Aerodigestive Tract Tissues.” Drug Metabolism and Disposition: The Biological Fate of Chemicals, vol. 48, no. 3, Mar. 2020, pp. 160–68. PubMed, https://doi.org/10.1124/dmd.119.089284.
Waszkiewicz, Napoleon, et al. “Serum β-Glucuronidase as a Potential Colon Cancer Marker: A Preliminary Study.” Postepy Higieny I Medycyny Doswiadczalnej (Online), vol. 69, Apr. 2015, pp. 436–39. PubMed, https://doi.org/10.5604/17322693.1148704.
Wu, Tien-Yuan, et al. “Pharmacokinetics and Pharmacodynamics of 3,3’-Diindolylmethane (DIM) in Regulating Gene Expression of Phase II Drug Metabolizing Enzymes.” Journal of Pharmacokinetics and Pharmacodynamics, vol. 42, no. 4, Aug. 2015, pp. 401–08. PubMed, https://doi.org/10.1007/s10928-015-9421-5.
Yang, Guangyi, et al. “Glucuronidation: Driving Factors and Their Impact on Glucuronide Disposition.” Drug Metabolism Reviews, vol. 49, no. 2, May 2017, pp. 105–38. PubMed, https://doi.org/10.1080/03602532.2017.1293682.
Zhou, Youyou, et al. “Association of UGT1A1 Variants and Hyperbilirubinemia in Breast-Fed Full-Term Chinese Infants.” PLoS ONE, vol. 9, no. 8, Aug. 2014, p. e104251. PubMed Central, https://doi.org/10.1371/journal.pone.0104251.
Originally published Jun 3, 2015