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, neurotransmittersestrogensmold toxinsglucuronidation, and cancer-causing toxins. During the glucuronidation process, glucuronidation glucuronic glucuronidation part of the UDP-glucuronic acid is transferred to the toxins to make them:.

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Glucuronidation

Federal government websites often end in. The site is secure. 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 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. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that though UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure. Glucuronidation is an enzyme reaction process catalyzed by UDP-glucuronosyltransferases i. Glucuronidation process attaches a glucuronide moiety to a substrate making a product that is highly hydrophilic Radominska-Pandya et al. The glucuronides are then often eliminated via bile or urine.

For these compounds, local glucuronidation does not play significant role in first pass metabolism, but the glucuronides can later participate in local recycling followed by excretion in lumen through bile Xia et al. In contrast to human, Ugt1a subfamily containing 10 different isoforms Ugt1a1, glucuronidation, 1a2, 1a3, 1a4, 1a5, glucuronidation, 1a6, 1a7, 1a8, 1a9, and 1a10while Ugt2b subfamily consists of six members, glucuronidation, namely, Ugt2b1, 2b2, 2b3, glucuronidation, 2b8, and 2b12 Mackenzie et al.

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. Hormones are glucuronidated to allow for easier transport around the body.

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. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver.

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. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure. Keywords: Glucuronidation; UGT; disposition; efflux transporters; glucuronides; interplay; recycling; uptake transporters. Abstract Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances.

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Decreased clearance found for codeine glucuronide, and decreased unbound clearance for oxazepam in the very elderly. Allele Effect AA More likely to have a reduced risk of developing colon cancer when taking aspirin AG No reduction in risk of developing colon cancer when taking aspirin GG No reduction in risk of developing colon cancer when taking aspirin rs The UGT1A6 gene plays a role in the glucuronidation of anthracycline metabolites used in cancer treatment. Hepatology 42 — Rifampin Tobacco smoking Phenobarbital. It was exactly what I was looking for and am planning on purchasing additional reports. Phase II metabolites of drugs such as glucuronides, once formed, uses efflux transporters to exit the cell. 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 compounds, including some with high aqueous solubility. May 30, Pharm Res 17 — Study of the glucuronidation processes started about the same time as the study of cytochrome P or CYP.

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OATP1B1 has been shown to play crucial role in the hepatic transport of glucuronides. Steroids 22 — BPA Bisphenol-A is a toxin present in plastic and known to cause diseases like breast cancer. Once formed in the intestinal epithelial cells, glucuronides are excreted into the portal vein by the efflux transporters in enterocytes, from where they enter hepatocytes with the aid of hepatic uptake transporters to be excreted into bile. Annu Rev Pharmacol Toxicol 54 — Introduction Glucuronidation Process. Many forms of the UGT1A1 gene are associated with conditions like Crigler-Najjar Syndrome, Gilbert syndrome, transient familial neonatal hyperbilirubinemia, etc. Graphs illustrating the driving forces for systemic distribution green and elimination orange of glucuronide in enterocytes a , hepatocytes b , and renal cells c. Rapid Commun Mass Spectrom 25 — During the glucuronidation process, the glucuronic acid part of the UDP-glucuronic acid is transferred to the toxins to make them:. Keywords: Glucuronidation, glucuronides, UGT, disposition, recycling, interplay, efflux transporters, uptake transporters. Local recycling can occur either independently or in conjugation with other recycling processes. Toggle limited content width. Carcinogenesis 22 —