The Importance of Local Chemical Structure for Chemical Metabolism by Human Uridine 5′‐Diphosphate—Glucuronosyltransferase.

Sorich, Michael J.; McKinnon, Ross; Miners, John O.; Smith, Paul A.

doi:10.1002/chin.200711223

Cited by 15 publications

(28 citation statements)

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“…In both HLM and rUGT, a similar trend was observed in terms of K m values, with all the imidazoles having higher affinity for UGT metabolism, along with itraconazole and posaconazole. In terms of structureactivity relationships, it has previously been reported that the steric and electronic character immediately local to the nucleophilic atom is an important predictor for glucuronidation (Sorich et al, 2006), and for many UGTs the attachment of an aromatic ring to the nucleophile and the type of nucleophile increases the likelihood for glucuronidation. From an evaluation of physicochemical properties, it was observed that all the imidazole nucleophiles were more basic than the triazoles (pK a 6.03-6.88 for imidazoles compared with 2.44 -2.94 for triazoles).…”

Section: Azole Glucuronidation In Hlm and Rugtmentioning

confidence: 99%

“…The most commonly described pathway is Oglucuronidation, which may have overshadowed N-glucuronidation as discussed during the 1996 ASPET "N-Glucuronidation of Xenobiotics Symposium" (Franklin, 1998). In an evaluation of the importance of local chemical structure for metabolism by UGT enzymes, most UGT isoforms were found to have a preference for oxygen over nitrogen glucuronidation, with the converse for UGT1A4 (Sorich et al, 2006). N-Glucuronidation may occur at various functional groups that include alkylamines, arylamines, hydroxylamines, carbamates, ureas, thioureas, and sulfonamides (Hawes, 1998).…”

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confidence: 99%

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Investigation into UDP-Glucuronosyltransferase (UGT) Enzyme Kinetics of Imidazole- and Triazole-Containing Antifungal Drugs in Human Liver Microsomes and Recombinant UGT Enzymes

Bourcier¹,

Hyland²,

Kempshall³

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:Imidazoles and triazoles represent major classes of antifungal azole derivatives. With respect to UDP-glucuronosyltransferase (UGT) enzymes, the drug metabolism focus has mainly concentrated on their inhibitory effects with little known about azoles as substrates for UGTs. N-Glucuronide metabolites of the imidazole antifungals, tioconazole and croconazole, have been reported, but there are currently no reports of N-glucuronidation of triazole antifungal agents. In this study, evidence for glucuronidation of azole-containing compounds was studied in human liver microsomes (HLM). When a glucuronide metabolite was identified, azoles were incubated in 12 recombinant UGT (rUGT) enzymes, and enzyme kinetics were determined for the UGT with the most intense glucuronide peak. Six imidazole antifungals, three triazoles, and the benzodiazepine alprazolam (triazole) were evaluated in this study. All compounds investigated were identified as substrates of UGT. UGT1A4 was the main enzyme involved in the metabolism of all compounds except for fluconazole, which was mainly metabolized by UGT2B7, probably mediating its O-glucuronide metabolism. UGT1A3 was also found to be involved in the metabolism of all imidazoles but not triazoles. In both HLM and rUGT K m values were lower for imidazoles (14.8-144 M) than for triazoles (158-3037 M), with the exception of itraconazole (8.4 M). All of the imidazoles studied inhibited their own metabolism at high substrate concentrations. In terms of UGT1A4 metabolism, itraconazole showed kinetic features characteristic of imidazole rather than triazole antifungals. This behavior is attributed to the physicochemical properties of itraconazole that are similar to those of imidazoles in terms of clogP.

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Section: Azole Glucuronidation In Hlm and Rugtmentioning

confidence: 99%

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confidence: 99%

Investigation into UDP-Glucuronosyltransferase (UGT) Enzyme Kinetics of Imidazole- and Triazole-Containing Antifungal Drugs in Human Liver Microsomes and Recombinant UGT Enzymes

Bourcier¹,

Hyland²,

Kempshall³

et al. 2010

Drug Metabolism and Disposition

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“…Nineteen functional human UGT proteins have been identified to date, and these have been classified in two families (1 and 2) and three subfamilies (UGT1A, UGT2A, and UGT2B) based on sequence identity . The individual UGT enzymes exhibit distinct, but overlapping, substrate and inhibitor selectivities (Radominska-Pandya et al, 1999;Tukey and Strassburg, 2000;Miners et al, 2004Miners et al, , 2006Kiang et al, 2005;Sorich et al, 2006).…”

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confidence: 99%

Influence of N-Terminal Domain Histidine and Proline Residues on the Substrate Selectivities of Human UDP-Glucuronosyltransferase 1A1, 1A6, 1A9, 2B7, and 2B10

Kerdpin¹,

Mackenzie²,

Bowalgaha³

et al. 2009

Drug Metabolism and Disposition

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ABSTRACT:An N-terminal domain histidine [corresponding to position 39 of UDP-glucuronosyltransferase (UGT) 1A1] is conserved in all UGT1A and UGT2B subfamily proteins except UGT1A4 (Pro-40) and UGT2B10 (Leu-34). Unlike most UGT1A and UGT2B xenobioticmetabolizing enzymes, UGT1A4 and UGT2B10 lack the ability to glucuronidate 4-methylumbelliferone (4MU) and 1-naphthol (1NP), both planar phenols, and naproxen (a carboxylic acid). However, only UGT1A4 glucuronidates the tertiary amines lamotrigine (LTG) and trifluoperazine (TFP). In this study, we sought to elucidate the influence of specific N-terminal histidine and proline residues on UGT enzyme substrate selectivity. The conserved N-terminal domain histidine of UGT1A1, UGT1A6, UGT1A9, and UGT2B7 was mutated to proline and leucine 34 of UGT2B10 was substituted with histidine, and the capacity of the wild-type and mutant proteins to glucuronidate 4MU, 1NP, LTG, TFP, and naproxen was character- UDP-glucuronosyltransferase (UGT) enzymes catalyze the covalent linkage of glucuronic acid, donated by the cofactor UDP-glucuronic acid (UDPGA), to a typically hydrophobic substrate bearing a suitable functional group according to a second-order nucleophilic substitution mechanism. Hydroxyl (aliphatic and aromatic), carboxylic acid, and amine (primary, secondary, and tertiary) functional groups most commonly serve as the nucleophilic "acceptor" for glucuronic acid (Miners and Mackenzie, 1991;Radominska-Pandya et al., 1999). Because a myriad of compounds fulfill these minimal requirements for metabolism by UGT, glucuronidation provides an elimination and detoxification pathway for many drugs, nondrug xenobiotics, and endogenous compounds. Nineteen functional human UGT proteins have been identified to date, and these have been classified in two families (1 and 2) and three subfamilies (UGT1A, UGT2A, and UGT2B) based on sequence identity . The individual UGT enzymes exhibit distinct, but overlapping, substrate and inhibitor selectivities (Radominska-Pandya et al

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“…Sorich et al (2006) and Peng et al (2014) reported SOM prediction models for UDP-glucuronosyl transferases (UGTs), and the Substrate Product Occurrence Ratio Calculator (Boyer et al 2007), MetaPrint2D (Adams, 2010) and Fast Metabolizer (Kirchmair et al 2013) were developed for the SOM prediction of global metabolism. The predictive power of the UGTs model appears reasonable, as reported by Peng et al whereas the predictive power of the SOM prediction model for global metabolism must be improved.…”

Section: Som Predictionmentioning

confidence: 99%

In silicoADME/T modelling for rational drug design

Wang

Xing

Yue

et al. 2015

Quart. Rev. Biophys.

281

155

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Abstract. In recent decades, in silico absorption, distribution, metabolism, excretion (ADME), and toxicity (T) modelling as a tool for rational drug design has received considerable attention from pharmaceutical scientists, and various ADME/T-related prediction models have been reported. The high-throughput and low-cost nature of these models permits a more streamlined drug development process in which the identification of hits or their structural optimization can be guided based on a parallel investigation of bioavailability and safety, along with activity. However, the effectiveness of these tools is highly dependent on their capacity to cope with needs at different stages, e.g. their use in candidate selection has been limited due to their lack of the required predictability. For some events or endpoints involving more complex mechanisms, the current in silico approaches still need further improvement. In this review, we will briefly introduce the development of in silico models for some physicochemical parameters, ADME properties and toxicity evaluation, with an emphasis on the modelling approaches thereof, their application in drug discovery, and the potential merits or deficiencies of these models. Finally, the outlook for future ADME/T modelling based on big data analysis and systems sciences will be discussed.

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The Importance of Local Chemical Structure for Chemical Metabolism by Human Uridine 5′‐Diphosphate—Glucuronosyltransferase.

Abstract: Computers in chemistry V 0380The Importance of Local Chemical Structure for Chemical Metabolism by Human Uridine 5'-Diphosphate-Glucuronosyltransferase. -(SORICH*, M. J.; MCKINNON, R. A.; MINERS, J. O.; SMITH, P. A.; J. Chem. Inf. Model. (J. Chem.

Cited by 15 publications

References 1 publication

Investigation into UDP-Glucuronosyltransferase (UGT) Enzyme Kinetics of Imidazole- and Triazole-Containing Antifungal Drugs in Human Liver Microsomes and Recombinant UGT Enzymes

Investigation into UDP-Glucuronosyltransferase (UGT) Enzyme Kinetics of Imidazole- and Triazole-Containing Antifungal Drugs in Human Liver Microsomes and Recombinant UGT Enzymes

Influence of N-Terminal Domain Histidine and Proline Residues on the Substrate Selectivities of Human UDP-Glucuronosyltransferase 1A1, 1A6, 1A9, 2B7, and 2B10

In silicoADME/T modelling for rational drug design

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