This page contains educational material primarily about the biotransformational pathway called gucuronidation. This information is for educational purposes only. Nothing in this text is intended to serve as medical advice. All medical decisions should be made only with the guidance of your own personal medical authority. I am doing my best to get this data up quickly and correctly. If you find errors in this data, please let me know.

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Glucuronidation or Glucuronosylation

Glucuronidation is a major pathway for transforming dietary toxins, drugs, carcinogens, and other environmental chemicals into less toxic substances. Glucuronidation is responsible for converting lipophilic (fat loving) xenobiotics and endogenous substances into metabolites that are more water soluble and therefore more easily excreted by the body in the urine or bile. Glucuronic acid conjugates are often excreted in the bile. This Phase II transformation/detoxification enzyme system predominates the Phase two conjugating systems in humans. Many drugs and diet-derived constituents are deactivated via glucuronidation. Polyphenolic molecules are extensively metabolized in the gut and liver with glucuronidation.

In glucuronidation, a glucuronic acid (a type of sugar) is attached to toxins to form more water soluble compounds that can be more easily excreted in the urine or in the bile. Although, the glucuronides formed are usually less toxic and inactive, they are not always. It is a major biotransformation pathway in mammals.

Glucuronidation requires the enzyme family, uridine diphosphate-glucuronosyltransferrases (UGTs) and the substrate or donor UDP-glucuronic acid (UDPGA). UDP-glucuronic acid links to a aglycone containing a nucleophilic functional group, leading to the creation of water soluble glucuronide conjugate and UDP.

There are 19 functional human UGTs classified into three subfamilies based upon structural and amino acid sequence homology, UGT1A, UGT2A and UGT2B. The UGTs are membrane-bound enzymes largely localized to the endoplasmic reticulum. Substrate specificity varies greatly between family members, with broad overlap, and their substrate specificity can be altered by posttranslational modifications such as phosphorylation. UGTs are largely found in the liver and intestines. However they are also in the prostate where they regulate local androgen levels by glucuronidation and in the breast where they regulate estrogens.

During glucuronidation, the enzyme uridine diphosphate-glucuronosyltransferrase catalyzes the conjugation of things such as free carcinogens and steroid homones to a glucuronic acid. The glucuronide-bound toxins and hormones are then safely excreted in the bile and the urine. Many of the commonly prescribed drugs are detoxified through this pathway.

Adults make about 5 grams of UDPGA per day. UDPGA has a short half life.

UGTs are predominately localized in the smooth endoplasmic reticulum of liver cells, but have also been found in a variety of other organs including the lung, kidney, and intestinal tract. (Mulder, 1992)

The main characteristic of UGTs is their ability to catalyze glucuronidation of a large array of structurally unrelated substances. Products of phase I reactions mediated by P450-dependent monooxygenases are major substrates of UGTs. Substances which possess the functional chemical groups that are readily glucuronidated are hydroxyl groups (phenols, alcohols), carboxylic acid groups (ester glucuronides), amine groups (N-glucuronides), and thiol groups (S-glucuronides). UGTs play a major role in the detoxification of xenobiotics, including drugs and environmental substances such as mycotoxins, as well as in the metabolism of endogenous compounds (bilirubin, steroid hormones, bile acids, fatty acids) (Rowland et al., 2013) Glucuronidation processes potentially carcinogenic environmental toxins such as polycyclic aromatic hydrocarbons and nitrosamines. In people, 40-70% of drugs are processed through glucuronidation. It helps to detoxify aspirin, menthol, vanillin (synthetic vanilla), and food additives such as benzoates. UGTs are involved in the glucuronidation of the monoamine neurotransmitters, dopamine (DA) and serotonin.

UGTs are most commonly found in the liver, kidneys, gut, lung and olfactory tissue.

Glucuronidation of Phenols - Examples are morphine, paracetamol (Competition between sulfation and glucuronidation is common for phenols.)

Glucuronidation of alcohols - Examples are chloramphenicol, propranolol

Glucuronidation of Carboxylic acids - Examples are furosemide, probenecid, salicylic acid, naproxen

Glucuronidation of Amines - Many drugs contain imidazoles, tetrazoles etc.


Some Substances Subject to Glucuronidation

Tetrahydrocannabinol, the primary psychoactive ingredient in marijuana, is subject to cytochrome P450 oxidation (primarily CYP2C9 and CYP3A4) and subsequent UDP-glucuronosyltransferase (UGT)-dependent glucuronidation. One research article showed glucuronide conjugation occurs for all classic cannabinoids tested and that classic cannabinoid metabolism seems to be tissue-specific.



This enzyme can undo the handy-work of glucuronidation. Beta-glucuronidase will break the glucuronide bond and release the toxins. This enzyme has been found in multiple body tissues and the blood. All glucuronides can be cleaved by B-glucuronidase except C-glucuronides. This may seem crazy if you do not know that beta-glucuronidase is used by the body to do other things than release toxins. Releasing toxins is just collateral damage. For example, beta-glucuronidase is involved with breaking down large molecules called glycosaminoglycans (GAGS). GAGS are long sugar molecules linked together and the sugars are removed one at a time. B-glucuronidase is involved in the break down of three types of GAGS called, dermatan sulfate, heparin sulfate and chondroitin sulfate. B-glucuronidase removes glucuronic acid from the end of the GAG chain.

A certain amount of beta-glucuronidase activity appears to be important for normal enterohepatic recirculation of endogenous compounds such as thyroid hormone, estrogen and vitamin D. It also appears to be important in the cell membranes for control of flavonoid conjugation/deconjugation during inflammation. However, deconjugation of toxins in the gut by beta-glucuronidase is not helpful. They have to stay conjugated to be removed in the feces.

Human β-glucuronidase has been found in all body fluids and mammalian tissues, with the highest activity in kidney, spleen, epididymis, liver, cancer tissue, and the gastrointestinal tract, (which is distinct from the β-glucuronidase produced by gastrointestinal tract microorganisms). Inside the cell, the beta-glucuronidase is found in the lysosomes which are compartments in the cells that digest and recycle different types of molecules. Beta-glucuronidase is imporatnt in recycling of old parts you could say.

Remember, glucuronides created from glucuronidation are excreted in the urine and bile. The glucuronides excreted in the bile may be hydrolyzed in the intestines by beta-glucuronidase and the unbound toxin can then be reabsorbed via the enterohepatic recirculation Toxins, hormones and drugs can be reabsorbed in this manner. If there is kidney disease and glucuronides are not being removed in the urine, they will be removed by the bile. In the case of kidney disease, it allows more of them to be hydrolyzed in the gut by beta-glucuronidase and be reabsorbed creating a toxic situation.

Beta-Glucuronidase And Reversible metabolism via enterohepatic cycling

There are three possible recycling processes that can keep a glucuronidated toxin in the system. First there is hydrolysis of the toxin in the gut. In this state as an aglycone, it is rapidly absorbed into the intestinal epithelial cells and travels to the hepatocytes eventually. Both the epithelial cells and hepatocytes use conjugation with glucuronic acid to appropriate aglycone forms and the glucuronide is then excreted via efflux pumps into the lumen of the gut or the bile as appropriate. Once in the bile these conjugated toxins can be hydrolyzed (unconjugated via hydrolysis) to their original aglycone form by bacterial created beta-glucuronidase in the colon or enteric beta-glucuronidase in the upper small intestine. This aglycone could then be subsequently reabsorbed again by the colon

The Three Types of Recycling Explained

The three types of recycling that an endogenous or exogenous substance may be able to participate in, which allows the substance to remain in the body longer. Enterohepatic recycling, enteric recycling, and local recycling.

Through these recycling, excreted conjugates can be deconjugated into their respective aglycone forms, followed by their intestinal reabsorption.

Enterohepatic recycling, involves the hepatic excretion of the glucuronides into the intestine via bile. The glucuronides can be hydrolyzed by bacteria-derived glucuronidase and reabsorbed into colon, thereby completing the enterohepatic recycling.

Enteric recycling, involves the intestinal excretion of glucuronides after they are taken up by the enterocyte. Enteric recycling needs bacterial β-glucuronidases in the colon to release aglycones from enterocyte-excreted conjugates.

Local recycling, a novel recycling mechanism proposed more recently, only requires enterocyte-derived β-glucuronidases to deconjugate the glucuronides in the upper small intestine, thereby completing the subsequent reabsorption and recycling loop without bacterial enzymes.

Things that are known

Glucuronides are susceptible to B-glucuronidase cleavage in the GI tract, which leads to their enteroheptic recycling - reverse metabolism. B-Glucuronidase in the gut is primarily a product of enteric bacteria. Glucuronides hydrolyze within a physiological ph range on the acid side.


Flavonoids and Beta-glucuronidase

Some researchers suggest that B-glucuronidase is a key enzyme for the bioactivation of the inactive flavonoid metabolites in the body. In vivo expression of B-glucuronidase has been associated with inflammation and inflammatory cells such as lymphocytes, kupffer cells (liver immune cells) and/or macrophages. It has been shown that normal endothelial cells, lining the inside of the blood vessel walls, the smooth muscle cells and extracellular matrix do not appear to usually accumulate flavonoids or their conjugated aglycones. However, atherosclerotic lesions in the blood vessels as well as the co-localized macrophage-derived foam cells do contain them. Researchers think that the increased permeability of the endothelial cells lining the blood vessels allows certain plasma molecules to permeate and interact with the intimal cells such as macrophages. This is the usual story of inflammation causing increased tight junction permeability. The co-localization of the flavonoids in the injured areas may be important for their antinflammatory and antiatherosclerotic activity at these sites.

Beta-glucuronidase is generally found near the UGT enzymes that catalyze glucuronidation. In vitro research shows that B-glucuronidase needs an acidic medium to be able to work. In addition macrophage cells stimulated by lipopolysaccharide endotoxin result in acidification when the cells secrete lactic acid as a result of glycolysis. The increased level of lactate is considered an indicator of mitochondrial dysfunction. It is thought that this increased lactate provides the correct Ph environment for B-glucuronidase to catalyze deconjugation of conjugated flavonoid metabolites.

Example of the flavonoid quercetin: In a recent study of the flavonoid quercetin, and the conjugated form called quercetin-3-O-glucuronide, when deconjugation activity was inhibited, there was a failure to inhibit the expressions of the pro-inflammatory genes, such as scavenger receptors and cyclooxygenase-2. However, the quercetin aglycone and/or the methylated forms did significantly inhibit the pro-inflammatory signaling pathways, such as the c-Jun N-terminal kinase pathway. This strongly suggests that the deconjugation of the conjugated metabolites is essential for the anti-inflammatory and anti-atherosclerotic activities inside the cells. Therefore, the primary accumulation of the glucuronides bound onto the cell surface proteins of the macrophages appears to be important for deconjugation into the aglycone on the cell surface, where the β-glucuronidase activity is concentrated and the Ph is lower from excretion of lactate from the mitochondrial dysfunction.

Although the potent mutagenicity and cytotoxicity of quercetin have been demonstrated in vitro, they have not yet been confirmed in vivo after the oral intake of quercetin. The safety of orally administered quercetin and other flavonoids in vivo may be explained by the fact that most flavonoids are metabolized during absorption and circulation. The phase II detoxification converts hydrophobic chemicals into hydrophilic metabolites, and then helps to limit the entry of the chemicals into cells. Indeed, the entry of quercetin-3-O-glucuronide into the macrophage cells was limited only to the cell surface. The conjugation (glucuronidation and/or sulfation) of hydroxyl group(s) on polyphenols attenuates the anti-oxidative and anti-inflammatory activities and promotes their rapid excretion. It has long been controversial whether the conjugated metabolites of the flavonoids can act as health-beneficial agents in vivo. As mentioned above, quercetin-3-O-glucuronide failed to inhibit the anti-inflammatory gene expressions in macrophages and the β-glucuronidase-mediated conversion of quercetin-3-O-glucuronide into the aglycone was essential for the inhibitory effects.The selective deconjugation within the sites of inflammation might ensure the safety of flavonoids in normal tissues.

In vitro research shows that autophagy (destruction and recycling of cell components) inducers reduced the β-glucuronidase activity, while autophagy impairment induced the β-glucuronidase activity. (Yoshichika Kawaik, 2014) Studies further demonstrated that mitochondrial dysfunction derived from autophagy/mitophagy impairment in the inflammatory cells could be implicated in the induction of chronic inflammation. These observations suggested that autophagy impairment could be a trigger for mitochondrial dysfunction that induces the β-glucuronidase activity.

Excessive Beta Beta-glucuronidase Activity

If you have excessive Beta-glucuronidase activity in your intestines, this would cause an increase recycling of toxins as mentioned above. Elevated beta-glucuronidase activity has been associated with increased cancer risk. Usually, when you slow down biotransformation processes, especially those of Phase II, you risk an increase in cancer.

Beta-glucuronidase is inducible by anaerobic E.coli, Peptostreptococcus, Bacteroides and clostridia. Using probiotics and prebiotics to increase the friendly gut bacteria and keep the unfriendly ones in check will help reduce beta-glucuronidase in the gut. Calcium-D-glucarate also inhibits the enzyme.

Administration of Calcium D-glucarate, a suppressant of beta-glucuronidase, has shown reductions in breast cancer risk in animal studies.

Calcium D-glucarate inhibits the deconjugation of glucuronides by inhibiting beta-glucuronidase. This supplement is used to enhance glucuronidation indirectly through inhibition of beta-glucuronidase. Some foods are also high in calcium D-glucarate. They include all of the mustard family vegetables such as broccoli, cabbage, Brussels sprouts, as well as apples, grapefruit and oranges.


Glucuronidation of Bilirubin

Bilirubin is a waste product from degradation of heme derived from blood cells. Glucuronidation of bilirubin is how fat-soluble free or unconjugated bilirubin is transformed by the liver into water soluble conjugated bilirubin to be eliminated in the bile. Glucuronidation of bilirubin also takes place in the intestines.

Bilirubin-IXalpha + UDP-Glucuronic Acid -----> (UDP-Glucluonosyltransferase and Mg++ needed for reaction) IXalphaC12 Bilirubin-B-Glucuornide + UDP.

Infants often have immature levels of glucuronidation, thus they can have unconjugated hyperbilirubinemia.


Genetics and Glucuronidation

As a general rule in most people, glucuronidation is thought to work well by mainstream medicine unless you have one of the rare genetic disease that can be harmful enough to necessitate a liver transplant.

I personally think that most people can use some help with glucuronidation in our current chemically taxed environment. I suggest ways to assist it below. There are some genetic polymorphisms with uridine diphosphate-glucuronosyltransferrase (UGT) enzyme mutations which give us an idea as to what takes place when glucuronidation is not working up to par. I am only going to talk about one of the more common ones below.

UGT1A1: This gene encodes UDP-glucuronosyltransferase (UGT), an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases.

The mutations in UGT1A1 gene result in several syndromes connected with decreased bilirubin detoxification capacity of UGT1A1. The most common deficiency of UGT1A1 is Gilbert's syndrome.


Genetics, Glucuronidation And Gilbert’s syndrome

Technical Data: Gilbert syndrome is caused by homozygous, compound heterozygous, or heterozygous mutation in the UDP-glucuronosyltransferase gene (UGT1A1; 191740) on chromosome 2q37.

The genotype in Gilbert's is UGT1A1*28/*28. A polymorphism in the promoter region of the UGT1A1 gene has been identified in the majority of Caucasian individuals with Gilbert syndrome (80-100%). These individuals are homozygous for two extra bases (TA) in the promoter region of the gene and have an A(TA)7TAA sequence rather than an A(TA)6TAA sequence. This change is associated with reduced expression of the UGT1A1 gene and thereby reduced levels of the UGT1A1 protein. The A(TA)7TAA allele is also known as UGT1A1*28.

The rs34815109(TA) allele represents the insertion variant, which actually adds a seventh (TA) pair to what is already a string of six (TA) pairs; this reduces the activity to 30% of normal, and is thus the risk allele. The risk allele is commonly referred to as the UGT1A1*28 allele, and it is homozygous in ~10% of the US population.

For more details, go to:




A missense change in the UGT1A1 gene, G71R, has been identified in approximately 30-40% of Asian individuals with neonatal hyperbilirubinemia and has been implicated in Gilbert syndrome in this population. This change is also associated with a decreased expression of the UGT1A1 gene. The frequency of the G71R allele is approximately 10% in the general Asian population. The G71R allele is also known as UGT1A1*6.

Gilbert’s syndrome is a relatively common syndrome characterized by a chronically, intermittent, elevated unconjugated serum bilirubin level (1.2-3.0 mg/dl). Previously considered rare, Gilbert's Syndrome is now known to affect about 5% (2-12%) of the general population. (These numbers change a bit from research to research article.) 16 percent of the population is homozygous for the long TATAA element, whereas only 2 to 12 percent of the general population have clinically diagnosed Gilbert's syndrome. The condition is usually thought by mainstream medicine to be without serious symptoms, although some patients do complain about loss of appetite, malaise, and fatigue (typical symptoms of impaired liver function).

I think the reason Gilbert's Syndrome has been considered to be a ("non -issue) is that the focus on these folks has been all about bilirubin. The problems seen with bilirubin were usually mild. As the focus turns to glucuronidation problems in removing toxins I think the idea of this being a syndrome without serious complications will disappear.

As mentioned, the UGT1A1 gene encodes a protein called UGT that modifies hepatic bilirubin in order to allow it to be excreted. Single-nucleotide polymorphisms (SNPs) that reduce the activity of the UGT1A1 gene therefore tend to increase serum bilirubin levels. However, also remember that UGT is needed for other glucuronidation transformations of small lipophilic molecules, such as mycotoxins, hormones, and drugs, into water-soluble, excretable metabolites.

I question if this is really a condition without serious symptoms. It may have been before we unleashed so many toxins in our environment, and before so many people were taking handfuls of prescription medications. Some people do have more serious symptoms and you can read about them at http://www.gilbertssyndrome.com The main way this condition is recognized is by a slight yellowish tinge to the skin and white of the eye due to inadequate metabolism of bilirubin, a breakdown product of hemoglobin. It is no surprise that people with Gilbert's syndrome may be predisposed to toxicity of drugs that use the glucuronidation pathway for drug elimination. The UGT1A1*28/*28 genotype has emerged as an important element in drug tolerance, glucuronidation of estrogens and some xenobiotics and may contribute to multifactorial diseases, such as cancer.

Dieting, dehydration, emotional stress or anxiety, heavy physical exercise or exertion and irregular sleep or sleep deprivation can cause people with Gilbert's syndrome to feel worse.

Increased cholesterol gallstones from abnormally low activity of hepatic bilirubin UDP-glucuronosyltransferase

Researchers have found an increase number of people with Gilbert's Syndrome who have gallstones and it is thought that the unconjugated bilirubin acts as a trigger for gallstone formation. One study found that low activity of hepatic bilirubin UDP-glucuronosyltransferase was found in 25% of patients with gallstones, as compared with only 3% in 35 controls.

People with Gilbert's syndrome have a similar amount of bilirubin in their bile, though concentrations of unconjugated bilirubin are higher. These unconjugated bilirubin monoglucuronides are thought to be the ones that create stones.

Schizophrenia and Bilirubin Factor

Moderate to high levels of unconjugated bilirubin (UCB) in the blood may lead to bilirubin being deposited in the central nervous system. Individuals with Gilbert's Syndrome have an increased prevalence of schizophrenia. When astrocytes (a kind of brain cells) are exposed to UCB they stimulate an immune response. This cytokine response reduces dendrite development, which is seen in schizophrenia. UCB disrupts several vital neural cellular functions, alters neural cell membranes, and decreases nerve cell viability.

More Genetics And UGT

The genetic variability in the UGT1 or UGT2 gene families was also suggested to alter risk of cancer either as a result of decreased inactivation of hormones such as estrogens or due to reduced detoxification of environmental carcinogens and their reactive metabolites (Guillemette, 2003) This is of course a very real concern that is being paid more attention to now by the alternatively minded medical community.

There are variants of UGT1A9 that appear to create a fast metabolizer phenotype in 15% patients.  

Interindividual variation in nicotine glucuronidation is substantial and glucuronidation accounts for from 0 to 40% of total nicotine metabolism. We report here the effect of a polymorphism in a UDP-glucuronosyltransferase, UGT2B10, on nicotine metabolism and consumption.

Polymorphisms in UGT1A9 promoter (T-275A and C-2152T) associated with increased hepatic 1A9 protein expression (Girard et al. 2004) have shown to decrease bioavailability of mycophenolic acid (immunosuppressive) when patient had either or both polymorphisms (Kuypers et al., 2005)

Non-carriers of the T-275A and C-2152T 1A9 promoter polymorphisms (low 1A9 expressors) showed a trend toward increased gastrointestinal toxicity  of mycophenolic acid.


Inducers, inhibitors and Substrates of Glucuronidation
There are known inducers and substrates for glucuronidation.

Substrate: A substance acted upon by an enzyme such as UGT. The substrate is the toxin, or hormone, or bilirubin that is to be acted on and undergoes glucuronidation.

Inducer: Something that activates UGTs or makes them work better or otherwise induces glucuronidation.

Inhibitor: Something that deactivates UGTs or otherwise decreases the enzyme from working as well or otherwise decreases glucuronidation.

Substrates and Inducers

Resveratrol (trans-3,5,4′-trihydroxystilbene), natural polyphenol in grapes, peanuts and other berries) is a substrate for glucuronidation as well as sulfation. This polyphenol has in vitro and in vivo research showing it can prevent both cardiovascular disease and cancer. It has ben shown to prevent and decrease progression of cancers such as breast, prostate, bladder, color, endometrial and skin cancer. However, it has a short half-life due to being metabolized quickly and has shown poor action in clinical trials. This has lead to research on how it is metabolized. No surprise that a major pathway is through glucuronidation. Two resveratrol glucuronides have been reported, resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide.

Relative to resveratrol, its glucuronidation and reduction metabolites showed equal, comparable, or some degree of activity in the above assays, depending on the specific compound and test model, which probably supports their roles in contributing to the in vivo biological activities of the parent molecule.

Pterostilbene (naturally occurring analog of resveratrol): Glucuronidation of Pterostilbene is much less efficient than that of resveratrol in people, meaning it should be more bioavailable Females are more efficient than males in glucuronidation of pterostilbene. Pterostilbene has been shown to be equally or significantly more potent than resveratrol in several biological assays in mice including inhibition of skin, colon,and liver cancer.

UGT1A1 and UGT1A3 are mainly responsible for pterostilbene glucuronidation although UGT1A8, UGT1A9 and UGT1A10 also had detectable activity. UGT1A1 exhibits the highest activity for both resveratrol and pterostilbene.

Curcumin is another substrate that undergoes glucuronidation. It has been shown that piperine found in black pepper inhibits glucuronidation in rats and guinea pigs. When piperine has been given to humans and rats it has enhanced the bioavailability of curcumin by 2000% in humans and 154% in rats. It is thought to be due to inhibition of glucuronidation by the piperine.

Research with purple rice bran extract showed the extract attenuated the aflatoxin B-1 induced initiation state of hepatocarcinogenesis by decreasing Phase I activity and protein expression of CYP1A2, CYP3A and CYP450 reductase, while enhancing the phase II enzymes including GST used for glutathione conjugation and UGT (uridine diphosphate-glucuronosyltransferrases) used for glucuronidation.

The activity of UDP-glucuronosyltransferase (UDPGT) is increased by foods rich in the monoterpene limonene (citrus peel, dill weed oil, and caraway oil).

Licorice (Glycyrrhiza spp.) has some conflicting data, but I provide some of it here. Licorice provides glucuronic acid. The constituent glycyrrhizic acid, is a conjugate of two molecules, namely glucuronic acid and glycyrrhetinic acid.

Concentration of UDP-glucuronic acid was increased 257% by Glycyrrhiza roots and 484% by glycyrrhizin. These data indicate that GR and glycyrrhizin activated glucuronidation and thus suggest the possibility that GR may influence detoxification of xenobiotics in rat liver.

Another study on Licorice found inhibitory activity on UGT when testing ingredients of licorice, liquiritin and liquiritigenin.

Another study on Licorice found 18beta-glycyrrhetinic acid induces UGT in rats. The results showed that the mRNA expression of UGT1A8 could be induced both by 18beta-glycyrrhetinic acid and the licorice extract. GA was identified to be the active component of the aqueous extract of licorice responsible for induction of UGT1A8 in the rat liver.

Magnesium is required for UGT activity.

Sulforaphane (SFN), an isothiocyanate found in the Brassicaceae family can inhibit the activities of several CYPs, thus potentially leading to reduced activation of pro-carcinogens. SFN induces UGT as well as other phase II enzymes, such as glutathione-S-transferase (GST), and Quinone oxio-reductase.

D-limonene has been shown to increase total CYP activity, intestinal and liver UGT activity in rats.

Drugs as inducers and substrates

Hepatic glucuronidation activities are increased after treatment with microsomal enzyme inducers, such as pregnenolone-16α-carbonitrile, 3-methylcholanthrene , and Aroclor 1254.

The effects of warfarin on glucuronidation were inhibitory for UGT1A1, 2B7, and 2B17, but activating for UGT1A3. Mixed effects were observed for UGT1A7 and 1A9. .

Things That Inhibit beta-glucuronidase and therefore favor glucuronidation

Calcium D-glucarate (a calcium salt that is found in some plants, such as apples, oranges, grapefruit, Brassicaceae family vegetables and alfalfa) suppresses the enzyme called beta-glucuronidase. Beta-glucuronidase is an enzyme that inhibits the glucuronidation process, breaking apart the bound toxins. When this happens in the intestines, it will unleash toxins being removed in the bile and they can be taken back up into the body again.

Probiotics Lactobacillus casei shirota, Bifidobacterium breve, Lactobacillus acidophillus, Lactobacillus GG and Bifidobacteria were shown to decrease beta-glucuronidase activity.

Prebiotics Lactulose and oligofructose-enriched inulin were also shown to decrease beta-glucuronidase activity.

Fructooligosaccharides act as a good substrate for bifidobacteria. A general high-fiber diet including both soluble and insoluble fiber should be beneficial. Inulin specifically is often sold in supplements and it is available in dandelion roots, burdock roots and elecampane roots.

Low or non-meat diet. Lacto-vegetarian diets are associated with reduced levels of beta-glucuronidase.

Environmental and drug inducers: cigarette smoking, birth control pills, Phenobarbital


Inhibitors of glucuronidation may expose a person to the ravages of toxins. Knowing what substances can cause inhibition is important.

When there is more than one compound that is transformed by a single enzyme, there is what is called competitive inhibition. In this case one compound is unable to be transformed due to the competition of the other compound. The compound being transformed will bind the active site of the enzyme and the other compound simply can't use it now.

An increase in toxins can also lead to what is called inhibition due to increased toxic load. I would not really call this inhibition but it does decrease enzymes available. It is simply a case of using up available enzymes faster than they can be made.

Drug molecules seldom inhibit glucuronidation with sufficient potency to overcome the low affinity and high capacity of the UDP-glucuronosyl transferases (UGTs). So, you will seldom see drugs causing clinically relevant UGT-mediated interactions with other drugs. (Williams et al., 2004). However, diet-derived constituents have shown greater inhibitory potency toward UGT activity than most drugs, including those considered prototypical UGT inhibitors. These drugs would include nonsteroidal anti-inflammatory agents, benzodiazepines, and immunosuppressants

That being said, some drug inhibitors of glucuronidation are aspirin and probenecid.

Structure-activity relationships suggest that compounds containing the flavonol backbone, which is a common structural feature of many diet-derived constituents, are candidate substrates and inhibitors of the UGT1A family

Capsicum annum (chili pepper) has been shown to increase levels of beta-glucuronidase in rats which will reverse glucuronidation.

Starvation or fasting as well as alcoholism may decrease UDPGA pools.

Piperine from black pepper has been shown to inhibit glucuronidation and is used in conjunction with curcumin to keep it from being metabolized via glucuronidation.

Vitamin A inhibits the activity of UDP-glucuronosyltransferases (UGTs) at high exposure in vitro. It is thought that this is a possible explanation for adverse effects of Vitamin A at high exposures. https://www.ncbi.nlm.nih.gov/pubmed/27359323

These diet derived substances were found to be potent inhibitors of intestinal glucuronidation in an in vitro setting: Milk thistle flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin, and silydianin) and associated extracts (silibinin and silymarin) and other, structurally diverse diet-derived constituents (naringin, naringenin, apigenin, kaempferol, quercetin, and EGCG) Kaempferol was the most potent inhibitor of UGT activity. Ginsenosides have also been implicated in this kind of research as inhibiting UGTs. (Please realize that this were studied in vitro and they are constituents of plants.) This may or may not relate to real life.) We need to further examine clinical research with whole plant products as well as constituents. Current clinical evaluation of diet-derived substances as inhibitors of glucuronidation, include garlic and milk thistle which have confirmed minimal or no interaction risk with the UGT1A substrates acetaminophen and irinotecan, respectively.


UGTs substrate selectivity:

UGT1A1 - bilirubin, estradiol 3- glucuronidation

UGT1A3 - hexafluoro-1alpha, 2 5-dihydroxyvitamin D3

UGT1A4 Trifluoperazine

UGT1A6 - serotonin 1-Naphthol

UGT1A9 Propofol

UGT2B7 Zidovudine, morphine

UGT2B15 S-Oxazepam

•10  UGT isoforms in human liver  - UGT2B17 absent in about 30% human livers  (1A and 2B families).
•4  isoforms in human intestine,  UGT1A1, 1A10, 2B7, 2B17.
•3  isoforms in human kidney, UGT1A6, 1A9 and 2B7.
•No UGT isoforms were detected in human lung.


Mycotoxins & Glucuronidation

Conjugation takes place via glucuronidation of deacetylated trichothecenes or hydroxy-aflatoxins, or glutathione conjugation of epoxides. Microbial flora participate generally in toxicological deactivation pathways such as hydrolysis of ochratoxin A or deepoxidation of trichothecenes.

Ochratoxin A

Ochratoxin A, a toxin produced by A. ochraceus, A. carbonarius, A. melleus, A. auricomus, A. alliaceus, A. petrakii and Penicillium verrucosum, is one of the most abundant and potent food-contaminating mycotoxin in the world. It is a nephrotoxin, hepatotoxin, immunosuppressant, and possibly carcinogenic for humans and associated to Balkan Endemic Nephropathy.

At the cellular level, endogenous glucuronic acid can be conjugated to the OTA phenolic group or carboxylic group under the catalytic reaction by uridine-diphosphate glucuronosyltransferase (UGT). OTA-conjugates have been detected in liver (8%–17%) and intestinal tissue (6%). The presence of glucuronide conjugates was also reported in bile of pigs upon feeding with OTA contaminated feed. However, in all these reports, OTA-glucuronides were determined indirectly by using β-glucuronidase hydrolysis. No direct or definite evidence for the formation of OTA-glucuronides as well as complete chemical configurations are available.

Trichothecene mycotoxins Deoxynivalenol and Zearalenone from Fusarium

Conjugates of fusarium mycotoxins are found in foods and are called "Masked toxins" as they are not tested for and not known they are in the food. They are formed by the plant as it conjugates mycotoxins to polar groups. Plants have their own phase II conjugation activities just as animals do. Conjugates commonly occur along with their parent compounds in food and animal feed. Deoxynivalenol-3-glucoside (D3G) and zearalenone-14-glucoside (Z14G) are the most common masked mycotoxins found in foods when tested. These compounds could be toxic themselves or they could be hydrolyzed to release the parent aglycone after ingestion causing increased exposure to mycotoxins that is not accounted for with conventional lab analysis which does not consider conjugates. Since specific intestinal bacteria have been shown to convert D3G into DON, this is a highly likely possibility. For this reason, masked mycotoxins should be considered when evaluating population exposure to mycotoxins in food.

DON absorption takes place mainly in the duodenum and in the small intestine. DON causes impairment of gut motility and appetite. Effects of DON are associated with neuroendocrine signaling, proinflammatory gene induction, disruption of the growth hormone axis and altered gut integrity. It appears to involve altered neuroendocrine signaling at both the enteric and central levels. It is implicated in reproduction disorders of animals and hyperestrogenic syndromes in humans. Elevation of serotonin levels in the gut could be related to the peripheral and central serotonergic effects of DON.

DON and ZEN are effectively deconjugated by the human colonic microbiota (remember beta-glucuronidase), releasing their toxic aglycones and generating yet unidentified catabolites. ZEN's metabolites Z14G and Z14S are quickly deconjugated by colonic microbiota. The aglycone is much less polar than Z14G and Z14S and is more readily absorbed. Additionally intestinal mucosal cells may convert ZEN into the more estrogenic Phase I metabolite alpha and beta ZOL.

The average rates of DON glucuronidation 76%, and there was 68% excretion in a human volunteer's urine. The investigation of formed glucuronides revealed DON-15-glucuronide as main conjugation product besides DON-3-glucuronide. Recently, for the first time in human urine a third DON-glucuronide was detected and the fate of ingested masked DON forms (3-acetyl-DON and DON-3-glucoside) was preliminary assessed.

The mean excretion rate of ZEN was determined to be 9.4%. ZEN was mainly present in its glucuronide form and in some samples ZEN-14-glucuronide was directly determined 3–10 hours after exposure.

Biotransformation of Zearalenone: Biotransformation takes place in two major pathways: Hydroxylation forms the phase-I-metabolites α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL), while conjugation of ZEN and its reduced forms with glucuronic acid and sulfate leads to the formation of typical phase-II-conjugation products.

ZEN toxic effects are largely due to its strong estrogenic activity. ZEN has been shown to be hepatotoxic, hematoxic, immunotoxic and genotoxic.

24 hour urine was analyzed following ingestion of 100 mg ZEN at once by a male volunteer (Mirocha et al., 1981). Zearalenone-glucuronide (ZEN-GlcA) and α-ZEL-GlcA were the main metabolites, besides a minor amount of β-ZEL-GlcA was excreted. All analytes were determined after enzymatic hydrolysis and neither free nor sulfated metabolites were detected. Using the concentrations of the urinary metabolites, it can be estimated that about 10–20% of the ZEN dose, was recovered in the 24 hour urine (Metzler et al., 2010). A study analyzing urine samples obtained from 163 US girls also detected predominantly ZEN and α-ZEL. However, only free metabolites were quantified as no enzymatic hydrolysis was performed (Bandera et al., 2011). The fecal excretion of ZEN and its metabolites was not examined in humans yet.

The 24 hour urine samples contained on average 0.39 μg/L total ZEN (range 0.30–0.59 μg/L) as reported in Fig. 3. This corresponds to a daily excretion of 0.94 μg and a rate of 9.4% (range 7.0–13.2%), when taking the urine volume (mean 2.42 L) into account. This is in the same range as in the experiment of Mirocha and coworkers (1981) where the total ZEN intake was 10.000 times higher (100 mg), whereof approximately 10–20% were recovered in the 24 hour urine (Metzler et al., 2010). However, in this single experiment ZEN was not ingested via naturally contaminated food and in an unrealistic high concentration.


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