Glycosidation of an Endothelin ETA Receptor Antagonist and Diclofenac in Human Liver Microsomes: Aglycone-dependent UDP-sugar Selectivity

Tang, Cuyue; Ma, Bennett

doi:10.1124/dmd.105.005801

Cited by 6 publications

(7 citation statements)

References 28 publications

(42 reference statements)

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“…Indirect proof for the glycosidic nature of the metabolite was delivered in incubation experiments with ␤-d-Glucosidase. Diclofenac itself was not accepted as a substrate for the conjugation reaction with glucose (data not shown), again in line with the work of Tang and Ma that showed the same effect in human liver microsomes [30].…”

Section: Discussionsupporting

confidence: 85%

Metabolism of diclofenac in plants – Hydroxylation is followed by glucose conjugation

Huber¹,

Bartha²,

Schröder³

2012

Journal of Hazardous Materials

131

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Section: Discussionsupporting

confidence: 85%

Metabolism of diclofenac in plants – Hydroxylation is followed by glucose conjugation

Huber¹,

Bartha²,

Schröder³

2012

Journal of Hazardous Materials

131

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“…Subsequent experiments by the same group with diclofenac glycosidation found a K i for UDP-Glc similar to the S 50 and K i values (∼2.0 mM) reported here with morphine as the aglycone but a lower K m (∼0.1 mM) for UDP-GlcUA (Tang and Ma, 2005). Differing cofactor K m values for AS-3201 glucuronidation and glucosidation by HLM and hyodeoxycholic acid glucuronidation and glucosidation by UGT2B7 have also been reported Toide et al, 2004;Tang and Ma 2005), suggesting that the selectivity and binding affinity of UDP-sugars may be aglycone dependent, possibly because of enzyme conformational changes that occur upon aglycone binding. Although this may provide an explanation for the differing results between studies, most, but not all, kinetic investigations of the glucuronidation reaction suggest that UDP-GlcUA binding to the UGT enzyme occurs first (Luukkanen et al, 2005).…”

Section: Discussionmentioning

confidence: 70%

“…Although this may provide an explanation for the differing results between studies, most, but not all, kinetic investigations of the glucuronidation reaction suggest that UDP-GlcUA binding to the UGT enzyme occurs first (Luukkanen et al, 2005). Furthermore, glucosidation studies with recombinant UGT enzymes expressed in insect cells, as used by Tang and colleagues (Tang et al, 2003;Tang and Ma, 2005), may be complicated by the expression of an endogenous glucosyltransferase (see Discussion).…”

Section: Discussionmentioning

confidence: 91%

Morphine Glucuronidation and Glucosidation Represent Complementary Metabolic Pathways That Are Both Catalyzed by UDP-Glucuronosyltransferase 2B7: Kinetic, Inhibition, and Molecular Modeling Studies

Chau

Elliot

Lewis

et al. 2014

J Pharmacol Exp Ther

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Morphine 3-b-D-glucuronide (M3G) and morphine 6-b-D-glucuronide (M6G) are the major metabolites of morphine in humans. More recently, morphine-3-b-D-glucoside (M-3-glucoside) was identified in the urine of patients treated with morphine. Kinetic and inhibition studies using human liver microsomes (HLM) and recombinant UGTs as enzyme sources along with molecular modeling were used here to characterize the relationship between morphine glucuronidation and glucosidation. The M3G to M6G intrinsic clearance (CL int ) ratio (∼5.5) from HLM supplemented with UDP-glucuronic acid (UDP-GlcUA) alone was consistent with the relative formation of these metabolites in humans. The mean CL int values observed for M-3-glucoside by incubations of HLM with UDP-glucose (UDP-Glc) as cofactor were approximately twice those for M6G formation. However, although the M3G-to-M6G CL int ratio remained close to 5.5 when human liver microsomal kinetic studies were performed in the presence of a 1: 1 mixture of cofactors, the mean CL int value for M-3-glucoside formation was less than that of M6G. Studies with UGT enzymeselective inhibitors and recombinant UGT enzymes, along with effects of BSA on morphine glycosidation kinetics, were consistent with a major role of UGT2B7 in both morphine glucuronidation and glucosidation. Molecular modeling identified key amino acids involved in the binding of UDP-GlcUA and UDP-Glc to UGT2B7. Mutagenesis of these residues abolished morphine glucuronidation and glucosidation. Overall, the data indicate that morphine glucuronidation and glucosidation occur as complementary metabolic pathways catalyzed by a common enzyme (UGT2B7). Glucuronidation is the dominant metabolic pathway because the binding affinity of UDP-GlcUA to UGT2B7 is higher than that of UDP-Glc.

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“…There is no evidence that such molecules occur naturally. Vertebrate UDPGTs employ UDPGA preferentially, but acyl glucoside and galactoside conjugates of xenobiotics have been reported. − However, two hydroxycarboxylic acid substrates undergo glucosidation exclusively at the phenolic or alcoholic OH group. , In rare instances, dependent on the species, an acyl glucoside can be a major metabolite . The stability of these glycosides in vivo and their reactivity with proteins do not appear to have been investigated.…”

Section: Structures and Biosynthesis Of Ags And Related Glycosidesmentioning

confidence: 99%

Acyl Glucuronides: Biological Activity, Chemical Reactivity, and Chemical Synthesis

et al. 2006

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which after mutarotation at C(1) may transfer the acyl group back to the 1R-OH. This has been conclusively demonstrated by NMR spectroscopy. 14,30 Other rearranged forms of AGs are also known. When the Mitsunobu synthesis 32 (see Synthesis) is used, lactones of type 5 are byproducts, sometimes in appreciable yields. The mechanism of formation is not clear but presumably involves cyclization of the first-formed intermediate ester. If there were an in vivo route to such lactones via free carboxyl acyl glucuronides, they would doubtless be potent acylating agents, transferring in this case the sugar along with the acyl residue.Concerning 1β-AGs of benzoic acids, the chemical stability/ reactivity may be predicted with some confidence by a Hammett correlation, 33 as discussed in detail later (NMR section). Some preliminary studies have been carried out on the computational chemistry modeling of the relative stabilities of the isomers of the AGs of 2-, 3-, and 4-trifluoromethylbenzoic acids. 34 For nonarylcarboxylic acids, the structure-reactivity is more complex. Certainly branching at the R-carbon is a factor leading to increased stability; thus the AGs of gemfibrozil 6, 35 clofibric acid 7 36 and valproic acid 8, 37 all doubly R-substituted, display long half-lives (from about 6-70 h in pH 7.4 buffer 37 ).AGs derived from NSAIDs such as naproxen 9 and ibuprofen 10 generally have half-lives from 1 to 4 h under the same conditions. 38 In such compounds, an additional complication is the different rates of rearrangement of the (R)-and (S)-AG diastereoisomers. In the case of 2-phenylpropanoic acid itself 11, 38 this rate was found to be about twice as fast for the (2R)as for the (2S)-AG epimer, and this ratio is typical of the 2-aryl propanoate class. Scheme 2. Possible Fates of AGs Scheme 3. Reactivity of Acyl Glucuronides a a Clearly the rearrangement (pathway 2) requires migration of the acyl group at least as far as O(3).

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Glycosidation of an Endothelin ETA Receptor Antagonist and Diclofenac in Human Liver Microsomes: Aglycone-dependent UDP-sugar Selectivity

Abstract: ABSTRACT:Following the finding that UGT2B7 catalyzes the transfer of the glycosyl group from both UDP-glucuronic acid (UDP-GlcA) and UDP-glucose (

Cited by 6 publications

References 28 publications

Metabolism of diclofenac in plants – Hydroxylation is followed by glucose conjugation

Metabolism of diclofenac in plants – Hydroxylation is followed by glucose conjugation

Morphine Glucuronidation and Glucosidation Represent Complementary Metabolic Pathways That Are Both Catalyzed by UDP-Glucuronosyltransferase 2B7: Kinetic, Inhibition, and Molecular Modeling Studies

Acyl Glucuronides: Biological Activity, Chemical Reactivity, and Chemical Synthesis

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