Glucuronidation

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Glucuronidation

Glucuronidation is a well-known phase II detoxification reaction that acts as a pathway for eliminating many drugs, endogenous substances substances produced by the body such as hormones, neurotransmitters , estrogens , mold toxins , and cancer-causing toxins. During the glucuronidation process, the glucuronic acid part of the UDP-glucuronic acid is transferred to the toxins to make them:. The process of glucuronidation occurs in the liver , and the compound UDP-glucuronic acid or Uridine Diphosphate glucuronic acid is an intermediary product formed in the liver. The primary role of any detoxification pathway is to neutralize any compound or molecule that can harm the body. When toxins are not efficiently eliminated, they build up in the body, causing tissue and organ damage and giving rise to diseases like cancer. Glucuronidation, is an essential detoxification pathway in the elimination of a large number of drugs , hormones, bile acids, hydroxysteroids, tobacco products, and other endogenous and xenobiotic compounds not produced by the body but found in it toxic compounds. UGT or glucuronidation enzymes can be found throughout the body. Though these enzymes are primarily found in the liver, they may also be found in organs like the kidney, brain, pancreas, placenta, and intestines. Since the liver is the primary organ of detoxification, most clinically used drugs, endogenous and xenobiotic compounds, are metabolized or broken down into smaller components here. In addition, some UGTs are located in the breast, where they work on inactivating estrogen and prevent prolonged exposure of breast cells to estrogen. The UGTs present in the brain protects the local tissues from harmful and toxic chemicals.

The drug once absorbed by intestinal cells enters the portal vein by the passive diffusion, whereas its glucuronides formed in the intestinal cell excrete on the basolateral side gut lumen by the efflux glucuronidation.

Glucuronidation is often involved in drug metabolism of substances such as drugs , pollutants, bilirubin , androgens , estrogens , mineralocorticoids , glucocorticoids , fatty acid derivatives, retinoids , and bile acids. These linkages involve glycosidic bonds. Glucuronidation consists of transfer of the glucuronic acid component of uridine diphosphate glucuronic acid to a substrate by any of several types of UDP-glucuronosyltransferase. UDP-glucuronic acid glucuronic acid linked via a glycosidic bond to uridine diphosphate is an intermediate in the process and is formed in the liver. The substances resulting from glucuronidation are known as glucuronides or glucuronosides and are typically much more water - soluble than the non-glucuronic acid-containing substances from which they were originally synthesised. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or feces via bile from the liver.

The liver is the principal site of drug metabolism for review, see [ 1 General references The liver is the principal site of drug metabolism for review, see [ 1]. Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically active—sometimes even Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically active—sometimes even more so than the parent compound. An inactive or weakly active substance that has an active metabolite is called a prodrug, especially if designed to deliver the active moiety more effectively. Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization; whatever the process, the goal is to make the drug easier to excrete.

Glucuronidation

Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases UGTs into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the polarized excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides.

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Journal of Clinical Psychopharmacology. The site is secure. Specifically, these enzymes are broadly but unevenly distributed throughout various cells, tissues and organs with heavy concentrations in the first-pass metabolism organs i. Open in a separate window. Kuhnle et al. The glucuronides are then often eliminated via bile or urine. S2CID Chem Biol Interact — Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases UGTs into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Similarly, deconjugation of SNglucuronide by gut microflora, results in high concentrations of SN locally, thereby causing severe delayed diarrhea Kaneda et al. Though they participate in the uptake process, their role in drug disposition is not yet understood van de Steeg et al. Jia et al. Possible triple recycling of ezetimibe glucuronide leads to prolonged local exposure in gut, resulting in more bioactivity at the site of action Kosoglou et al. Hepatology 30 — Download as PDF Printable version.

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AAPS J 17 — In hepatocytes, MRP2 and BCRP are located on the canalicular membrane, where they function as efflux pumps to move intracellular glucuronides into bile Fig 1b. Glucuronidation is a phase II biotransformation reaction in which glucuronide acts as a conjugation molecule and binds to a substrate via the catalysis of glucuronosyltransferases. What Is Alcohol Detoxification? Collectively, the MRP family of efflux transporter is first known to convene resistance to anticancer agents Kock and Brouwer, Abstract Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. J Pharm Pharmacol 55 — Pharmacologists have linked drugs to glucuronic acid to allow for more effective delivery of a broad range of potential therapeutics. The conjugation of xenobiotic molecules with hydrophilic molecular species such as glucuronic acid is known as phase II metabolism. Local recycling can occur either independently or in conjugation with other recycling processes. Biopharm Drug Dispos 29 — On the other hand, alternative mechanisms such as random ordered bi bi mechanism were also reported, where binding of the substrate to the enzyme does not require prior binding to UDPGA Yin et al. Tissue Distribution of UGTs. Pharmacogenet Genomics 18 —