Glucuronidation is an important detoxification reaction that inactivates and detoxifies estrogens, hormones, neurotransmitters, drugs, mold toxins, and cancer-causing toxins. In this post, we’ll explain glucuronidation and factors that increase or decrease it. In addition, we’ll also cover beta-glucuronidase, an enzyme produced by gut bacteria that undoes glucuronidation. Finally, we’ll review the genes that affect glucuronidation.
What Is Glucuronidation?
Glucuronidation involves the addition of glucuronic acid to a toxic molecule to make it [1]:
- More water soluble
- Less toxic or reactive
- Easily transported throughout the body
- Possible to eliminate via urine
Why Is Glucuronidation Important?
If toxins don’t get properly inactivated and removed, they cause cell and tissue damage and may initiate cancer.
Glucuronidation is one of the most important detox reactions taking place in our bodies [2].
It is responsible for the clearance of many drugs, cancer-causing chemicals, environmental toxins, and substances found in food [3].
Where Glucuronidation Takes Place
Glucuronidation enzymes (UGTs) are found throughout the body: in the gut, kidney, brain, pancreas, and placenta. However, the majority are found in the liver [3].
This is because the liver is the key organ for processing drugs and internal compounds such as hormones and bile acids [4].
On the other hand, some UGTs (UGT2B15 and UGT2B17) are found in the prostate where they control local testosterone levels [5].
Others (UGT1A10 and UGT2B7) are found in the breasts where they inactivate estrogen [5].
In the brain, UGTs actively protect against the intrusion of harmful chemicals [2].
Dopamine and serotonin are also processed by UGTs. However, the impact of UGTs on the overall dopamine and serotonin levels is minor [2].
Key Glucuronidation Enzymes (UGTs)
Enzymes responsible for glucuronidation are called UDP-glucuronosyltransferases or UGTs [2].
In humans, around 40 – 70% of all clinical drugs are cleared by UGTs [3].
Apart from removing foreign substances, UGTs also participate in the clearance of bilirubin, steroid hormones, thyroid hormones, bile acids, and fat-soluble vitamins [3].
There are 19 functional human UGTs. They belong to one of the three subfamilies: UGT1A, UGT2A, and UGT2B [5].
What Gets Glucuronidated
Toxins from Foods and Environments
- Cancer-causing substances called polycyclic aromatic hydrocarbons, including benzo[a]pyrene, are found in cigarette smoke, wood smoke, and burnt foods [6, 7]
- BPA (Bisphenol-A), is a toxin used in plastics and linked to various human diseases including breast cancer [8]
- Some cancer-causing nitrosamines are found in tobacco smoke and in the gut of people who eat red meat [9]
- Heterocyclic amines (HACs) are found in red processed meat; PhIP is the most abundant one, found in well-done cooked meat, and it is inactivated by UGT1A enzymes [10]
- Some fungal toxins are found in moldy crops [11]
Hormones, Bile Acids, Neurotransmitters, and Vitamins
- Estrogen [12]
- Androgens (including testosterone) [5]
- T3 and T4 [13]
- Bilirubin [3]
- Bile acids [3]
- Fat-soluble vitamins [3]
- Dopamine and serotonin (minor role) [2]
Factors That May Increase Glucuronidation (UGTs)
1) Cruciferous Veggies/Sulforaphane
Sulforaphane, found in cruciferous vegetables (with the highest levels in broccoli sprouts), increases glucuronidation [14, 15].
Research suggests It’s the most potent inducer of phase 2 detox enzymes (including UGTs) identified to date. It acts by activating Nrf2 [16, 17]. Nrf2 then activates UGTs.
PhIP is a cancer-causing agent present in cooked food. A study with 20 non-smoking men found that brussels sprouts and broccoli increased PhIP glucuronidation [18].
A diet enriched in cruciferous or cruciferous plus apiaceous vegetables also increased glucuronidation (UGT1A1) in another study with 70 subjects [19].
2) Watercress
A study in 12 smokers found that watercress increases UGT enzyme activity [20].
3) Citruses
Citruses may especially benefit people with certain gene variants.
In a study with healthy nonsmokers (293 subjects), citruses increased UGT1A1 activity by about 30%, but only in women with two copies of the UGT1A1*28 variant [21]. This is the variant associated with lower UGT1A1 activity and Gilbert’s syndrome.
4) Other
These herbs and supplements increased glucuronidase activity in animal studies:
- Soy [22]
- Green tea [23, 24]
- Dandelion [25]
- Rooibos tea [26]
- Honeybush tea [26]
- Coffee [27]
- Rosemary (particularly UGT1A6) [28]
- Ellagic acid (found in walnuts, pecans, berries, grapes, and pomegranate) [29]
- Ferulic acid (found in coffee and whole grains) [29]
- Quercetin (found in many fruits and veggies, capers, onions, berries, and tea) [29]
- Tannic acid [29]
- Coumarin (found naturally in many plants like tonka bean, cassia cinnamon, and vanilla grass) [29]
- Fumaric acid [29]
- Curcumin (turmeric, found in curry powder) [29]
- Flavone [29]
- Astaxanthin and canthaxanthin (carotenoids) [30]
It’s important to stress that what’s found in animal studies, doesn’t always match what’s later found in humans. The findings from animal studies are given solely for information purposes and will be updated as soon as new findings from human studies become available.
There are a lot more foods and supplements that increase UGTs in isolated liver or gut cells. However, these results are often inconclusive and don’t translate well into animal or human studies.
Factors That May Decrease Glucuronidation (UGTs)
1) Piperine
Piperine (from black pepper) inhibits UGTs (glucuronidation enzymes) in rats and mice [31, 32, 33].
However, in the studies above, piperine decreased the clearance of curcumin, resveratrol, and green tea. This is considered beneficial because it increases their bioavailability.
Adding black pepper may be a good way to increase curcumin, resveratrol, and green tea exposure and their health benefits.
2) Drugs
Analgetics, nonsteroidal anti-inflammatory drugs (NSAIDs), antiviral drugs, anticonvulsants, and anti-anxiety meds/sedatives can decrease UGT activity [3].
3) Other
A wide variety of foods and supplements decrease UGTs in isolated cells. These include curcumin, ginger extract, quercetin, silybin, ginseng, vitamin A, green tea, and its component epigallocatechin gallate (EGCG) [34, 35, 36, 37, 38]. However, these do not necessarily work in the same manner in living organisms.
For example, milk thistle is a strong glucuronidation inhibitor in isolated cells [39, 40]. However, in humans, it didn’t have a significant effect [41].
What Is Beta-glucuronidase?
Beta-glucuronidase is an enzyme produced by gut bacteria (such as E. coli) and gut cells [42].
This enzyme reverses the glucuronidation reaction and reactivates the inactivated toxins to their previous active form [42].
Research has found a link between elevated beta-glucuronidase activity and an increased risk of various cancers, such as colon cancer, and hormone-dependent breast and prostate cancers [43, 44].
Factors That Increase Beta-glucuronidase
1) High-Fat Diet
A study in 279 people suggests that those with higher total and saturated fat intake have higher beta-glucuronidase activity (279 subjects) [45].
2) Being Overweight
The same human study found a link between being overweight (BMI ≥ 25) and having higher beta-glucuronidase activity [45].
3) Being Male
Studies suggest that men may have more of this enzyme than women [45, 46].
4) Aging
Researchers found that as we get older, beta-glucuronidase activity increases [46].
5) Smoking
A study in 100 people suggests that smoking may increase this enzyme [47].
6) Disease – Liver Inflammation and Colon Cancer
Researchers have found an increased activity of this enzyme in many diseases: liver inflammation, liver cirrhosis, jaundice, tuberculosis, and cancer [48].
Beta-glucuronidase activity was 1.7 times higher in colon cancer patients compared to healthy people [49].
In fact, this enzyme may be a sensitive indicator pointing to cell and tissue damage [48].
7) Other
Drugs like phenobarbital and spironolactone were shown to increase this enzyme in rats [50].
However, more studies are needed to confirm the same effect in humans.i
Factors That Decrease Beta-glucuronidase
1) A Plant-Rich Diet
A study in 279 people found that those who consumed more plants had generally lower beta-glucuronidase [45].
Another study also showed that this enzyme was lower with a higher intake of plant protein, fruit, and dietary fiber (203 subjects) [51].
Beneficial plants were those belonging to the gourd family (such as squash, pumpkin, zucchini, cucumber, and watermelon), the rose family (apples, pears, plums, cherries, peaches, raspberries, and strawberries), and legumes (peas and beans) [51].
However, another study with 63 volunteers found an increase in this enzyme on a diet enriched with crucifers, citrus, and soy [52].
2) Vitamin C, Calcium, Iron, and Magnesium
In an initial study with 18 people, vitamin C decreased beta-glucuronidase activity by 25% [53].
The above study in 279 people found that those with higher dietary intakes of calcium, iron, and magnesium had lower beta-glucuronidase activity [45].
4) Probiotics
The probiotic L. helveticus decreased beta-glucuronidase activity in elderly volunteers [54].
L. casei and B. breve also showed a tendency to decrease this enzyme (53 healthy volunteers) [55].
In mice, lactic acid bacteria (L. brevis, L. acidophilus or B. longum) lowered this enzyme [56].
Finally, L. rhamnosus decreased this enzyme in mice treated with cancer-causing PhIP [57].
5) Prebiotics/Fiber
Prebiotics are basically fibers that stimulate the growth of beneficial bacteria in our bodies.
A study with 53 healthy volunteers showed that consuming prebiotics (lactulose or oligofructose-enriched inulin) decreased beta-glucuronidase activity [55].
6) Other
These decreased beta-glucuronidase activity in animal studies:
- Caloric restriction in rats and monkeys [58, 59]
- Blackcurrant in rabbits on high-fat diet [60]
- Strawberry pulp extract in rats [61]
- Black pepper in rats exposed to colon-cancer-causing chemicals [62]
- Cumin in rats exposed to colon-cancer-causing chemicals [62]
- Calcium-D-glucarate (D-glucaric acid) in rats [63]. D-glucaric acid is found in many fruits and vegetables, with the highest levels in grapefruit, apples, oranges, and cruciferous vegetables. It is transformed in the stomach into D-glucaro-l,4-lactone, a natural inhibitor of beta-glucuronidase activity [44, 64].
- Lower colon pH [65, 66]
These decrease beta-glucuronidase in isolated cells:
- Licorice (G. uralensis) [67]
- Milk thistle (silymarin) [68]
- Reishi mushroom (G. lucidum) [69]
- Green tea (epigallocatechin gallate) [70]
- B. infantis [71]
- Kombucha [72]
Again, what’s found in cell and animal studies, doesn’t always match what’s later found in humans. The findings from animal and cell studies are given solely for information purposes and will be updated as soon as new findings from human studies become available.
Can Genes Predispose to Worse Glucuronidation?
Over 10% of the population have hereditary deficiencies in UGTs [73].
There is a single UGT1 gene that produces all UGT1A1 family members. Depending on how the enzyme is later processed, it becomes one of the 9 UGT1A enzymes [74, 75].
The UGT2 family enzymes are all produced by separate genes [74].
Limitations
Before we dive into the research associated with glucuronidation, keep in mind that most of the studies below are largely based on association, suggesting that certain genetic variants are more or less common in people with these conditions. More research is needed to know what role, if any, these variants play in actually contributing to conditions such as heart disease, osteoporosis, and cancer.
In addition, all these conditions are dependent on a multitude of factors, and UGT variants may have only a minor effect. Therefore, just because you may have a certain UGT variant, that doesn’t necessarily mean you are at an increased or decreased risk of developing these conditions!
UGT1A
RS8330
This is a variant in the shared part of the UGT1 gene (it is present in all UGT1A enzymes).
Studies suggest that people with this variant may clear Tylenol (paracetamol) from their system better [76].
UGT1A1
UGT1A1 is the only enzyme that glucuronidates bilirubin.
It also inactivates some cancer-causing compounds and estrogen.
Patients with a rare inherited disorder called Crigler-Najjar syndrome have a complete or partial absence of this enzyme [3].
Complete UGT1A1 absence results in high levels of bilirubin, severe jaundice, and brain damage in infants. Those with a partial deficiency have milder jaundice and generally survive into adulthood without neurological or intellectual impairment [3].
Gilbert’s syndrome is a mild disorder caused by a mutation in the UGT1A1 gene. People with this syndrome have mildly elevated bilirubin levels [3].
Gilbert’s syndrome is found in about 10% of the population [3].
People with Gilbert’s syndrome also have reduced clearance of drugs like Tylenol [74].
RS34815109
This variant is also known as the UGT1A1*28 variant (also rs8175347, rs3064744 or rs35600288).
It is the most common cause of Gilbert’s syndrome. UGT1A1*28 occurs with a frequency of 26-31% in Whites, 42 – 56% of African Americans, and only 9 – 16% of Asians [77].
This variant results in 30 – 40% lower UGT1A1 levels [78].
Studies suggest that when people with this variant eat food containing cancer-causing chemicals, such as well-done red meat, less of the cancer-causing chemicals from the meat get deactivated [78].
A study in 765 people found that having two copies of UGT1A1*28 was associated with higher odds of having lung cancer [79].
Similar associations have been found for UGT1A1*28 and breast cancer (240 and 2130 subjects), and colon cancer (168 subjects) [80, 81, 82].
On the other hand, UGT1A1*28 was associated with lower odds of having Crohn’s disease (751 patients and 930 controls) [83].
Additionally, a Framingham Heart study showed that people with two UGT1A1*28 copies had a 2/3 lower risk of developing heart disease over the 24 year follow-up period (1780 subjects) [84].
This relationship with heart disease, however, has not been confirmed in two other studies [77].
UGT1A6
Studies suggest that UGTs1A6 is responsible for the detox of cancer-causing agents such as benezo[a]pyrene from cigarette smoke [85].
UGT1A6 also inactivates Tylenol, aspirin, estradiol, and serotonin (in small amounts) [86, 87].
RS6759892
RS6759892 is also known as the UGT1A6*2 variant.
It was long thought to cause decreased UGT1A6 enzyme activity [86]. However, more recent studies have found that people with this variant actually process aspirin faster [88].
A study in 474 colon cancer patients and 563 healthy people found that NSAID use was associated with lowering the risk of colon cancer, but only in those carrying this variant [89].
Another study in 1062 women found the same for aspirin [90].
On the other hand, a study of 7418 cancer patients and 8,720 controls found that having two copies of this variant (GG) was associated with a higher risk of breast cancer [86].
Another study in 95 lung cancer patients and 100 controls found that this variant was associated with a higher risk of lung cancer [85].
UGT1A62 is often inherited together with UGT1A128, which may affect the association with cancer.
UGT1A7
This enzyme is found in the gut and the lungs [91].
UGT1A7 is involved in inactivating cancer-causing agents present in tobacco smoke [92].
RS17868323
This variant is also known as UGT1A7*3. It has lower detox activity [93].
A meta-analysis of 22 studies with over 9000 people found that UGT1A7*3 was associated with increased risk of liver, lung, and bladder cancer risk in Asians [94].
This variant has also been linked with chronic pancreas inflammation and pancreatic cancer in a study of 433 people [93].
UGT2B15
RS1902023
This variant is known as the UGT2B15*2 variant.
People with this variant seem to have a decreased clearance of Tylenol (paracetamol) (66 subjects) [95].
UGT2B17
UGT2B17 is one of the most commonly missing genes in humans [96].
Some people have two copies, while others have a single copy or don’t have this enzyme at all [97].
UGT2B17 deletion is more common in Asians (67%) than Whites (9%) [98].
This enzyme inactivates steroid hormones, including testosterone and estradiol. It also inactivates a large number of drugs and toxins [97].
People without UGT2B17 have higher levels of testosterone (by 15%) and estradiol [99, 100].
Men with higher testosterone levels are less likely to be obese. Accordingly, a study of 940 people found that men without UGT2B17 had lower BMI [100].
On the other hand, not having UGT2B17 has been associated with an increased risk of prostate cancer based on two meta-analyses (meta-analysis of 6 studies, 3,839 cases, and 3,190 controls) (meta-analysis of >25 studies, >17,000 subjects) [101, 102].
However, there is a study that found no association of UGT2B17 deletion and cancer risks (meta-analysis, 14 studies, 5,732 cases, and 5,112 controls) [103].
A study of over 2.3k women found that those without UGT2B17 tended to have higher bone mineral density [104].
Accordingly, a genome-wide copy variation study of over 3k people has found a link between UGT2B17 and osteoporosis [99].
A study suggests that those having one or two UGT2B17 copies, and therefore, lower estrogen levels, may benefit from hormone replacement therapy (2,379 women) [104].
However, there are also studies that found no link between UGT2B17 and osteoporosis (1,347 elderly women) [105].
