Glucuronidation: UGT genetic variants, phase II detoxification

The UGT family of enzymes are 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 such as pollutants or prescription medications enter your body, the substances are broken down and then eliminated. 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.

UGT Enzymes: Glucuronidation

The UDP-glucuronosyltransferase (abbreviated UGT) enzymes facilitate a glucuronidation reaction. This is just a term that means that one of the UGT enzymes helps to make a substance more water-soluble so that it can be excreted 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.

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 ]
  • cortisol
  • 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:

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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 Gene:

UGT1A1 is involved in the breakdown of bilirubin, estrogen, and several carcinogens. Bilirubin is a  product naturally created in the body 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 the 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.

There is a common variant known as UGT1A1*28 that is associated 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: normal

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: normal

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: normal

Members: Your genotype for rs6742078 is .

Check your genetic data for rs8330 (23andMe v5; AncestryDNA):

  • C/C: normal
  • 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: normal
  • 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 Gene:

UGT1A6 is also involved in transforming bilirubin, hormones, and certain drugs (aspirin, acetaminophen) into water-soluble metabolites that can then be excreted from the body.  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: normal

Members: Your genotype for rs17863783 is .

UGT1A9 gene:

Check your genetic data for rs6714486 (23andMe v4 only)

  • A/A: higher activity [ref ] [ref ]
  • T/T: normal

Members: Your genotype for rs6714486 is .


Lifehacks:

If your genetic data shows that you have slower than normal UGT activity, you may want to look into the following:

Speeding 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) have recently been shown to inhibit UGT1A1.[ref ]

Gut Microbiome Connection

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.

Lower levels of β-glucuronidase are linked to a lower risk of colon cancer.[ref ][ref ]

A recent study looked at the effect on β-glucuronidase from increasing the amount 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 Genes and Topics:

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.

Originally published Jun 3, 2015



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.