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Glucuronidation: UGT genetic variants, detoxification, and hormone balance

Key takeaways:
~ The UGT family of enzymes is an essential part of phase II detoxification.
~ Genetic variants in the UGT genes can affect your detoxification of BPA, estrogens, testosterone, and bilirubin.
~ Certain foods, like cruciferous vegetables,  or supplements can upregulate this pathway.

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.

Members will see their UGT genotype report below, plus additional solutions in the Lifehacks section. Join today 

Glucuronidation, phase II detoxification:

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When foreign substances enter the body, such as toxicants or prescription medications, the body breaks them down and eliminates them in a two-step process called phase I and phase II detoxification. Phase I detoxification uses the CYP450 enzymes to make the substance more polar. Then in phase II, the toxic substance is altered again to make it water-soluble so that it can be easily excreted from the body.

Overview: Detoxification: Phase I and Phase II Metabolism

Phase II detoxification is where the UGT genes come into play.

The UGT (UDP-glucuronosyltransferase) enzymes facilitate a glucuronidation reaction. Glucuronidation helps make certain toxic substances more water-soluble and able to be excreted through urine or feces.

This is important because the phase I detoxification metabolites are often more toxic and can cause oxidative stress or DNA damage. You don’t want the phase I metabolites hanging around, damaging cells or DNA. Thus, this phase II glucuronidation process needs to act in sync with phase I, making the substance water-soluble and quickly eliminated.

Glucuronidation involves the attachment of a glucuronic acid molecule to a toxicant or drug metabolite. Glucuronic acid is a metabolite of glucose and is abundant in the body.

The enzymes responsible for this process are called UDP-glucuronosyltransferases, or UGTs for short.

toxic metabolite + glucuronic acid + UGT enzyme  =  non-toxic, excretable

Where does glucuronidation occur?

Glucuronidation reactions are used by the body to inactivate and eliminate:

  • Bilirubin (from the breakdown of old red blood cells)
  • Retinoids (vitamin A components)
  • Hormone metabolites:
    • estrogens and testosterone[ref]
    • thyroid hormone (T3, T4) [ref]
    • cortisol
  • BPA and BPS[ref][ref]
  • certain fatty acids (DHA, oleic acid, linoleic acid)[ref]
  • 40 – 70% of medications[ref], including acetaminophen (Tylenol)[ref]
  • certain pesticides[ref]
  • polycyclic aromatic hydrocarbons (PAHs, carcinogenic)[ref]
  • certain mold toxins[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 or mold toxins.

What are the UGT genes?

There are 20 UGT genes that encode different UGT enzymes, each with its own specific substrates and functions.[ref] Some of the most well-studied UGT genes include:

UGT1A1: This gene is responsible for the glucuronidation of bilirubin, a breakdown product of red blood cells. Variants in UGT1A1 can lead to Gilbert’s syndrome, a condition characterized by mildly elevated bilirubin levels. UGT1A1 also plays a role in the metabolism of certain drugs, such as irinotecan, a chemotherapy agent.

Gilbert’s Syndrome involves bilirubin not being broken down appropriately.[ref] This syndrome leads to periodic 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.

Related article: Gilbert’s Syndrome

UGT1A6: This enzyme 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. Genetic variations in UGT1A6 may influence an individual’s risk of acetaminophen-induced liver toxicity and the effectiveness of certain NSAIDs.

UGT2B7: This enzyme is involved in the glucuronidation of various drugs, including morphine, codeine, and zidovudine (an HIV medication). Genetic variants in UGT2B7 can affect an individual’s response to these medications.[ref]

UGT2B15: This gene is responsible for the glucuronidation of testosterone and other androgens. Variants in UGT2B15 have been associated with differences in testosterone levels and prostate cancer risk.[ref] UGT2B15 is also involved in the metabolism of tamoxifen.[ref]

BPA is also eliminated, in part, using glucuronidation. One study found that UGT2B15 metabolizes up to 80% of BPA when concentrations are low, such as our normal daily exposure, but that another enzyme (UGT1A9) becomes more important at higher BPA levels.[ref]

It’s important to note that while genetic variants influence glucuronidation, other factors such as age, sex, diet, and liver function also play significant roles.

Odor detection, COVID loss of smell, and the UGT genes:

Interestingly, the UGT genes also interact with odor molecules in the nose. The UGT enzymes are expressed in the cells lining the nose. When an odor molecule is glucuronidated (using a UGT enzyme), it no longer activates odor receptors, thus turning off the signal to the brain that you smell something. This ‘turning off’ of the smell means that things you smell are more transient – instead of a constant signal that lasts for a long time. Something we can be grateful for when it comes to bad odors!

Why is this so interesting?
New research shows that the inability to smell things (anosmia) as a result of Covid may be linked with genetic variants in the UGT genes. While the difference based on the specific SNP identified in the study isn’t big (11% increased relative risk of anosmia), the mechanism of action indicated by the genetic findings is interesting. And no, the SNP identified in the study is not in 23andMe or AncestryDNA data.[ref]

UGT Genotype Report:

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Lifehacks: Natural solutions for slow UGTs

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

Upregulating glucuronidation and the UGT enzymes:

Member Content:

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Why join Genetic Lifehacks?

~ Membership supports Genetic Lifehack's goal of explaining the latest health and genetics research.
~ It gives you access to the full article, including the Genotype and Lifehacks sections.
~ You'll see your genetic data in the articles and reports.

Join Here

Related Articles and Topics:

Gilbert’s Syndrome:
Variants in the UGT genes cause higher bilirubin levels. Learn all about Gilbert’s syndrome here.

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.



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Originally published Jun 3, 2015

About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering from Colorado School of Mines and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.