China
Africa
Explore chapters and articles related to this topic
Opioids Analgesics and Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
R. Rachana, Tanya Gupta, Saumya Yadav, Manisha Singh
In the process of metabolization of morphine, it undergoes phase-I metabolism and phase-II metabolism. After the morphine has been administered to the patients via nebulizer or is taken orally, subcutaneously or intravenously, under phase-I metabolism, it is majorly metabolized via oxidation or hydrolysis in the liver and leads to the alteration in plasma levels. After this stage only, 40–50% of the morphine spreads to the CNS and within 72 h. 80% morphine dose is excreted via urine (Trescot et al., 2008). Then it undergoes, phase-II metabolism where it is metabolized by glucuronidation that is, the transfer of glucuronic acid component of uridine diphosphate glucuronic acid to a substrate in the presence of UDP-glucuronosyltransferase. The metabolizing process leads to synthesis of morphine-3-glucuronide and morphine-6-glucuronide in a ratio of 6:1 (Lotsch and Geisslinger, 2001), which are the two important metabolic morphine pathways in humans. The principal enzyme for morphine metabolism is UGT2B7 [uridine diphosphoglucuronosyl transferases (UGT)] which is primarily released by liver, but can be released by brain and kidneys, as well (Chau et al., 2014) However, the meaningful clinical effect of hydromorphone metabolite of morphine is still unknown (Fig. 19.2).
The Role of Conjugating Enzymes in the Biliary Excretion of Bilirubin
Published in Karel P. M. Heirwegh, Stanley B. Brown, Bilirubin, 1982
The identification of “direct reacting” bilirubin in bile coincided with the classical studies of Dutton and Storey, in which they showed that various alcohols and acids could be converted to glucuronide conjugates by a microsomal enzyme (UDP-glucu-ronate glucuronyltransferase; EC 2.4.1.17) with uridine diphosphate glucuronic acid (UDPGA), as the glucuronyl donor.1,2 It was therefore not surprising that a year later there were several publications3–5 announcing that a microsomal enzyme was responsible for the synthesis of bilirubin glucuronide in several animal species and that the presence of UDPGA was essential. The conditions for optimum conjugation differed slightly from those for o-aminophenol, and it was postulated that (1) at least two UDP-glucuronyltransferases existed and (2) a deficiency of bilirubin glucuronyltransferase was responsible for jaundice in the newborn rather than a limited production of UDPGA.5
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In the overall heme synthesis, δ-aminolevulinic acid production is the rate-limiting step. There are marked differences in the synthesis of heme, however, between various cells within one organism. Red blood cells contain 1000 times more heme molecules than hepatic cells, indicating probably the action of a nonenzymatic mechanism besides enzyme effects in the regulation of heme synthesis pathway.141,142 The intra- and extramitochondrial localization of participating enzymes suggests the existence of such a regulation mediated through differential permeability of mitochondrial membranes to key intermediates or differences in compartmentalization, end-product repression, or direct inhibition. The availability of the precursors glycine and succinyl-CoA, limitation of pyridoxal phosphate, and a reciprocal end-product feedback action of hemoprotein appears to be essential in the synthesis control mechanism. Another important regulating mechanism may be associated with the fact that mitochondrial δ-aminolevulinic acid synthetase is an inducible enzyme, and its levels are influenced by inducers of drug metabolism.242,243 Hydrocortisone stimulates the activity of this enzyme in adrenalectomized animals. This hepatic effect may be associated with alterations in the endoplasmic reticulum necessary for hepatic enzyme induction. The increased mitochondrial enzyme production is also mediated by changes in the endoplasmic reticulum.120,121,554,555 In contrast to the rise in porphyrin synthesis, the presence of additional enzyme pathways metabolizing intermediates may decrease heme formation. The oxidation of porphobilinogen to 5-oxo-porphobilinogen by porphobilinogen oxidase,186 or a protease which specifically breaks down pyridoxal phosphate requiring enzymes,317 may play such a role. Inhibition of heme biosynthesis is caused by hemin, hemoglobin, or bilirubin.214–216,421 These substances block the conversion of the soluble δ-aminolevulinic acid synthetase into the mitochondrial bound form. Drug-induced porphobilinogenuria could be prevented by increased intake of glucose in the diet. Glucose inhibits the induction of 8- aminolevulinic acid synthetase.456,488 The action of glucose is probably related to the transformation to uridine diphosphate glucuronic acid which converts porphyria-inducing substances such as corticosteroids to inactive glucoronide conjugates.
UDP-glucuronosyltransferase 1A4-mediated N2-glucuronidation is the major metabolic pathway of lamotrigine in chimeric NOG-TKm30 mice with humanised-livers
Published in Xenobiotica, 2021
Shotaro Uehara, Yuichiro Higuchi, Nao Yoneda, Hiroshi Yamazaki, Hiroshi Suemizu
Lamotrigine N2-glucuronidation activity by liver microsomes was measured as described previously (Argikar and Remmel 2009), with some minor changes. A typical incubation mixture (0.25 mL) contained either 0.5 mg/mL of recombinant human UGT1A4 supersomes or 0.5 mg/mL of liver microsomes, along with 0.057–10 mM lamotrigine, and 100 mM potassium phosphate buffer (pH 7.4), 5 mM MgCl2, and 100 μg/mg alamethicin. The incubation mixtures were pre-incubated at 37 °C for 3 min in a low-speed shaking water bath. The reaction was initiated by the addition of 5 mM uridine diphosphate glucuronic acid. After incubation at 37 °C for 10 min, the reaction was terminated by adding an equal volume of ice-cold acetonitrile containing 8-CPT (internal control). These samples were mixed and centrifuged at 20000 ×g for 10 min at 4 °C. The de-proteinated samples were analysed using liquid chromatography–tandem mass spectrometry (LC–MS/MS).
Glucuronidation of icaritin by human liver microsomes, human intestine microsomes and expressed UDP-glucuronosyltransferase enzymes: identification of UGT1A3, 1A9 and 2B7 as the main contributing enzymes
Published in Xenobiotica, 2018
Li Wang, Xiaodan Hong, Zhihong Yao, Yi Dai, Guoping Zhao, Zifei Qin, Baojian Wu, Frank J. Gonzalez, Xinsheng Yao
Uridine diphosphate glucuronic acid (UDPGA), magnesium chloride (MgCl2), alamethicin and D-saccharic-1, 4-lactone were provided from Sigma-Aldrich (St Louis, MO). Pooled human liver microsomes (HLM), pooled human intestine microsomes (HIM) and recombinant expressed human UGT Supersomes™ (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 2B4, 2B7, 2B10, 2B15 and 2B17) were obtained from Corning Biosciences (New York, NY). Icaritin (purity > 98%) were purchased from Jingzhu Medical Technology Co., Ltd (Nanjing, China). Chenodeoxycholic acid (CDCA), propofol and zidovudine (AZT) were purchased from Aladdin Chemicals (Shanghai, China). All other chemicals and reagents were analytical grade or the highest grade commercially available.
Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies
Published in Expert Opinion on Drug Discovery, 2018
Bence Szilágyi, György G. Ferenczy, György M. Keserű
Compound 14 was identified as DAAO inhibitor by virtual screening followed by measuring inhibitory activity for isolated human DAAO enzyme [57]. The X-ray structure of the complex has been determined (PDB: 3ZNP) [68]. Interestingly, the flexibly Tyr224 residue adopts a conformation more resemble to that in the free enzyme than in the benzoate complex. 14 has high nanomolar DAAO activity and increases D-Ala level in cultured mammalian cells [57]. It was later shown to be subject of high degree of glucuronidation in mouse liver microsomes in the presence of uridine diphosphate glucuronic acid [62].