UDP-glucuronosyltransferase (UGT) enzymes are a family of proteins that play an important role in the body’s detoxification processes. These enzymes are found predominantly in the liver, but also in other tissues like the kidneys, intestines, lungs, and brain. UGTs function by attaching glucuronic acid, a specific sugar molecule, to various compounds. This action helps the body modify and clear substances, acting as a defense mechanism against potentially harmful accumulations.
The Glucuronidation Process
Glucuronidation is a metabolic process carried out by UGT enzymes, serving as a primary method for the body to eliminate compounds. It involves transferring a glucuronic acid molecule from a donor compound, uridine diphosphate glucuronic acid (UDPGA), to a target substance. Many compounds are fat-soluble, making them difficult to excrete through watery fluids like urine or bile. The addition of glucuronic acid effectively acts as a “water-soluble tag” or handle.
Once tagged, these modified compounds, known as glucuronides, can be easily dissolved in bodily fluids. This enhanced solubility allows them to be transported and excreted through the kidneys in urine or via the liver into bile, preventing their buildup. Glucuronidation is a major component of Phase II detoxification, a pathway that neutralizes and prepares substances for removal.
Substances Processed by UGT Enzymes
UGT enzymes are versatile, processing various compounds, both internal and external.
Bilirubin
Bilirubin is a yellow waste product formed when old red blood cells break down. UGT1A1 converts fat-soluble unconjugated bilirubin into a water-soluble form. If this conversion is impaired, bilirubin can accumulate, leading to a yellowish discoloration of the skin and eyes, known as jaundice. Proper UGT1A1 function ensures bilirubin is cleared, maintaining healthy levels.
Pharmaceuticals
UGT enzymes are involved in metabolizing many medications, influencing drug processing and elimination. Approximately 40-70% of commonly prescribed drugs undergo glucuronidation. This step determines a drug’s effectiveness, duration of action, and appropriate dosage. For instance, the chemotherapy drug irinotecan is metabolized by UGT1A1, and enzyme variations can affect how quickly the drug is cleared, affecting its safety and efficacy.
Hormones
UGT enzymes also regulate and eliminate the body’s hormones. Steroid hormones, such as estrogen and testosterone, are conjugated by UGTs, controlling their levels and activity. This prevents excessive hormone accumulation, contributing to hormonal balance. Bile acids and thyroid hormones also undergo glucuronidation.
Environmental Toxins
UGT enzymes process environmental toxins and pollutants. This includes chemicals like polycyclic aromatic hydrocarbons and mycotoxins. By converting these harmful substances into water-soluble forms, UGTs facilitate their excretion. This helps protect the body from adverse effects.
Genetic Influence on UGT Activity
Genetic variations can impact UGT enzyme activity. These variations, called genetic polymorphisms, can lead to enzymes with altered activity. These differences explain varying responses to medications or waste product processing rates.
The UGT1A1 gene is a key example. Variations in this gene affect bilirubin processing efficiency. The UGT1A1 28 allele, a common polymorphism, contains an extra TA repeat in the gene’s promoter region and reduces UGT1A1 enzyme activity by approximately 30-70%.
This reduced activity causes Gilbert’s syndrome, a common and usually harmless condition affecting 5-10% of the U.S. population. Individuals with Gilbert’s syndrome may experience mild, intermittent elevations in unconjugated bilirubin, often without symptoms. Understanding UGT1A1 variations is also important in personalized medicine, especially for patients receiving cancer drugs like irinotecan. Patients homozygous for the UGT1A1 28 allele have reduced ability to clear irinotecan’s active metabolite, SN-38. This can increase their risk of severe side effects like neutropenia and diarrhea.
Factors That Modify UGT Function
External factors can alter UGT enzyme activity. These modifications can either increase (induction) or decrease (inhibition) enzyme activity. Understanding these interactions is important for managing drug efficacy and avoiding adverse effects.
Enzyme induction occurs when substances cause the body to produce more UGT enzymes, speeding up the metabolism of other compounds. For example, compounds in cruciferous vegetables, like sulforaphane, can increase UGT enzyme activity, enhancing detoxification. Some medications can also induce UGT activity, leading to faster clearance of other co-administered drugs.
Enzyme inhibition happens when a substance slows UGT enzyme activity, often by competing for the enzyme’s binding site. This can lead to the accumulation of substances that rely on the inhibited UGT for metabolism. Drugs like atazanavir, gemfibrozil, and indinavir are known to inhibit UGT1A1, which can affect the metabolism of drugs like irinotecan. Some dietary components, such as compounds in citrus fruits, can also influence UGT activity in specific genetic variations.