Glucuronidation

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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

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.

Toxicol Appl Pharmacol —

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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.

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A drug undergoing enterohepatic recycling usually shows the multiple-peak phenomenon in its plasma-concentration—time profile and the prolonged elimination half-life Gao et al. J Pharmacol Exp Ther :2—9. Aaps J 12 — Curr Drug Metab 15 — In sandwich-cultured human hepatocytes and membrane vesicle uptake assays, the involvement of MRP3 and MRP4 in hepatic transport of mycophenolic acid glucuronide into the circulation was reported Matsunaga et al. AAPS J 17 — Date of experience: March 01, Absorption, metabolism and excretion of [ringC]magnolol in rats. The site is secure. Individuals having two alleles of the mutated gene have a higher metabolic activity than those with the wild type the most commonly found allele in a population. On the other hand, glucuronides in portal vein may be taken up by the hepatocytes with the aid of hepatic sinusoidal uptake transporters. Two variations or single nucleotide polymorphisms — SNPs in this gene are rs and rs

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Related Posts. Ramanathan et al. Carcinogenesis 22 — The MRPs are the major efflux transporter family for phase II metabolites, and these transporters are expressed in many epithelial cells Bera et al. For example, morphineglucuronide is reported to be 45—61 folds more potent Frances et al. Ezetimibe Ezzet et al. In vast majority of the cases, these reactions occur in a polarized cell, making the glucuronide excretion polarized and dependent on the distribution of efflux transporter on two polar surfaces of a differentiated cell Fig 1. I bought the fitness, sleep and nutrition, and it makes so much sense for me and is very helpfull. Methods Mol Biol — Mechanisms of Glucuronidation. ISBN Cancer Res 50 — In hepatocytes, glucuronides are either excreted by apical efflux transporters such as MRP2 and BCRP into bile, or they enter the systemic circulation by basolateral efflux transporters such as MRP3 Fig 1c.