Glucuronidation

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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.

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. Hormones are glucuronidated to allow for easier transport around the body. Pharmacologists have linked drugs to glucuronic acid to allow for more effective delivery of a broad range of potential therapeutics. Sometimes toxic substances are also less toxic after glucuronidation. The conjugation of xenobiotic molecules with hydrophilic molecular species such as glucuronic acid is known as phase II metabolism. Glucuronidation occurs mainly in the liver , although the enzyme responsible for its catalysis , UDP-glucuronyltransferase , has been found in all major body organs e.

Though these enzymes are primarily found in the liver, they may also glucuronidation found in organs like the kidney, glucuronidation, brain, pancreas, placenta, and intestines. Introduction Glucuronidation Process.

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 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.

Glucuronidation

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. Drug metabolism rates vary among patients.

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Drug Metab Rev 38 — Routledge and Shand, ; Marshall et al. Eur J Nutr 45 — The glucuronosyltransferases UGTs then catalyze the transfer of glucuronic acid from UDPGA to a substrate resulting in a glucuronidated substrate and leaving uridine 5'-diphosphate. It's neat to have this kind of validation and proof! However, there are different mechanism among different model substrates and even different OATPs e. From hepatocytes, both intestinal- and hepatic-generated glucuronides are then excreted into bile and systemic circulation by the apical and basolateral hepatic efflux transporters, respectively. OATP transporters show varied expression levels on the apical or basolateral side of various human tissues. Tissue Distribution of UGTs. Table 3.

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Do not hesitate, go here, let them analyze your DNA, top notch service!!! Mrp1 is highly expressed in the intestine and certain other organs such as liver Cherrington et al. Wang et al. Am J Clin Nutr 76 — BSEP exclusively effluxes monoanionic conjugated bile acids, and whether it will excrete any other anions such as glucuronides remains to be determined. Some were metabolites of its aglycone. Pharmacol Ther — Clin Pharmacol Ther 92 — One hypothesis offered a possible explanation to the mechanism. The circulation half-life of a glucuronide can be prolonged as the result of the increased enterohepatic recycling. The interplay can happen between enzyme system UGT1A and UGT2B and efflux transporters both apical and basolateral in enterocytes and hepatocytes as well as between the efflux and uptake transporters of hepatocytes Liu and Hu, ; Jiang and Hu, ; Kock and Brouwer, ; Wu, ; Pfeifer et al. Although not frequently reported, hydrophilic molecules are sometimes also glucuronidated.