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

Stachulski, Andrew V.; Harding, John; Lindon, John C.; Maggs, James L.; Park, B. Kevin; Wilson, Ian D.

doi:10.1002/chin.200714257

Cited by 22 publications

(62 citation statements)

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“…Acyl glucuronides, which are enzymatic products formed by glucuronidation of carboxylic acids (Stachulski et al, 2006), are capable of undergoing the following: 1) hydrolysis to parent aglycone mediated by b-glucuronidases, nonspecific esterases, hydroxyl ion, or serum albumin; 2) intramolecular acyl migration to form positional isomers that are resistant to b-glucuronidase-mediated hydrolysis; and 3) covalent binding to proteins via transacylation or glycation mechanisms (Regan et al, 2010). Acyl glucuronides, however, differ widely in their chemical reactivity, which is attributed to the chemical structure of the aglycone moiety (Stachulski et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Acyl glucuronides, however, differ widely in their chemical reactivity, which is attributed to the chemical structure of the aglycone moiety (Stachulski et al, 2006). Postulated mechanisms for the toxicity of acyl glucuronides include the following: 1) a direct impairment of the function of a key protein that is covalently modified; 2) an indirect immune reaction to the antigenic drug-protein adducts; and 3) formation of more reactive acyl-glutathione thioester conjugates with intracellular glutathione (GSH), resulting in GSH depletion and possibly covalent binding to proteins (Shipkova et al, 2003;Skonberg et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Glucuronidation is a major metabolic pathway for VPA and contributes to the biotransformation of about 30-50% of the administered dose of VPA in humans (Silva et al, 2008). Valproyl 1-O-b-acyl glucuronide (VPA-G) is one of the least reactive acyl glucuronides investigated to date (Stachulski et al, 2006). Yet, it undergoes intramolecular acyl migration to form positional isomers of VPA-G (Dickinson et al, 1984) and appears to be responsible, at least partly, for the formation of VPA-protein adducts in vitro in rat hepatocytes (Porubek et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

2014

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Acyl glucuronides are reactive electrophilic metabolites implicated in the toxicity of carboxylic acid drugs. Valproyl 1-O-b-acyl glucuronide (VPA-G), which is a major metabolite of valproic acid (VPA), has been linked to the development of oxidative stress in VPA-treated rats. However, relatively little is known about the toxicity of in situ generated VPA-G and its contribution to VPA hepatotoxicity. Therefore, we investigated the effects of modulating the in situ formation of VPA-G on lactate dehydrogenase (LDH) release (a marker of necrosis), BODIPY 558/568 C 12 accumulation (a marker of steatosis), and cellular glutathione (GSH) content in VPA-treated sandwich-cultured rat hepatocytes. VPA increased LDH release and BODIPY 558/568 C 12 accumulation, whereas it had little or no effect on total GSH content. Among the various uridine 59-diphospho-glucuronosyltransferase inducers evaluated, b-naphthoflavone produced the greatest increase in VPA-G formation. This was accompanied by an attenuation of the increase in BODIPY 558/568 C 12 accumulation, but did not affect the change in LDH release or total GSH content in VPA-treated hepatocytes. Inhibition of in situ formation of VPA-G by borneol was not accompanied by substantive changes in the effects of VPA on any of the toxicity markers. In a comparative study, in situ generated diclofenac glucuronide was not toxic to rat hepatocytes, as assessed using the same chemical modulators, thereby demonstrating the utility of the sandwich-cultured rat hepatocyte model. Overall, in situ generated VPA-G was not toxic to sandwich-cultured rat hepatocytes, suggesting that VPA glucuronidation per se is not expected to be a contributing mechanism for VPA hepatotoxicity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

2014

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“…1-O-␤-Acyl glucuronides, which are formed by UDP-glucuronosyltransferase (UGT) enzymes as the original isomer, can undergo a number of reactions including hydrolysis, rearrangement via acyl migration (Stachulski et al, 2006;Zhang et al, 2006;Xue et al, 2008), further metabolism (Kumar et al, 2002;Kochansky et al, 2005;Ogilvie et al, 2006), and reaction with nucleophiles (Sallustio and Foster, 1995;Akira et al, 2002;Bailey and Dickinson, 2003). The chemical reactivity of acyl glucuronides proceeds via two distinct pathways (Bailey and Dickinson, 2003;Stachulski et al, 2006;Corcoran et al, 2001): 1) direct displacement of the acyl residue with a nucleophile to produce an aglycon (hydrolysis product) and an acylated nucleophile; and 2) alternatively, migration of the acyl group around the sugar ring to yield 2-, 3-, and 4-acyl isomers. These isomers may undergo transient ring opening with concurrent formation of a reactive aldehyde group.…”

Section: Introductionmentioning

confidence: 99%

Plasma Stability-Dependent Circulation of Acyl Glucuronide Metabolites in Humans: How Circulating Metabolite Profiles of Muraglitazar and Peliglitazar Can Lead to Misleading Risk Assessment

et al. 2010

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ABSTRACT:Muraglitazar and peliglitazar, two structural analogs differing by a methyl group, are dual peroxisome proliferator-activated receptor-␣/␥ activators. Both compounds were extensively metabolized in humans through acyl glucuronidation to form 1-O-␤-acyl glucuronide (AG) metabolites as the major drug-related components in bile, representing at least 15 to 16% of the dose after oral administration. Peliglitazar AG was the major circulating metabolite, whereas muraglitazar AG was a very minor circulating metabolite in humans. Peliglitazar AG circulated at lower concentrations in animal species than in humans. Both compounds had a similar glucuronidation rate in UDP-glucuronic acid-fortified human liver microsomal incubations and a similar metabolism rate in human hepatocytes. Muraglitazar AG and peliglitazar AG were chemically synthesized and found to be similarly oxidized through hydroxylation and O-demethylation in NADPH-fortified human liver microsomal incubations. Peliglitazar AG had a greater stability than muraglitazar AG in incubations in buffer, rat, or human plasma (pH 7.4). Incubations of muraglitazar AG or peliglitazar AG in plasma produced more aglycon than acyl migration products compared with incubations in the buffer. These data suggested that the difference in plasma stability, not differences in intrinsic formation, direct excretion, or further oxidation of muraglitazar AG or peliglitazar AG, contributed to the observed difference in the circulation of these AG metabolites in humans. The study demonstrated the difficulty in doing risk assessment based on metabolite exposure in plasma because the more reactive muraglitazar AG would not have triggered a threshold of concern based on the recent U.S. Food and Drug Administration guidance on Metabolites in Safety Testing, whereas the more stable peliglitazar AG would have.

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“…The metabolism of xenobiotics containing carboxylic acid groups to acyl glucuronides is a well known biotransformation reaction (recently reviewed in Skonberg et al, 2008;Stachulski et al, 2006). Acyl glucuronide metabolites have received considerable attention due to evidence suggesting that they are chemically reactive, form adducts with proteins, and potentially cause various toxicities via this mechanism (Yang et al, 2006;Skonberg et al, 2008).…”

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confidence: 99%

Glycerolysis of Acyl Glucuronides as an Artifact of in Vitro Drug Metabolism Incubations

Obach

2009

Drug Metab Dispos

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ABSTRACT:During an investigation of the in vitro glucuronidation of benoxaprofen by human liver S-9 fraction, an unusual drug-related entity possessing a protonated molecular ion that was 74 mass units greater than the parent drug was observed. It was identified as the glycerol ester of benoxaprofen. Formation of this entity required inclusion of uridine diphosphoglucuronic acid (UDPGA) in the incubation, suggesting the formation of benoxaprofen acyl glucuronide followed by transesterification with the glycerol present in the incubation due to its presence as a stabilizer for liver subcellular fractions. Formation occurred during the sample work-up procedure while the samples were subjected to evaporation in vacuo, which does not remove glycerol. Conversion of purified benoxaprofen acyl glucuronide to the glycerol ester was demonstrated in glycerol at 37°C. Other drugs that are converted to acyl glucuronides in vitro (diclofenac, mefenamic acid, tolmetin, and naproxen) were also shown to form corresponding glycerol esters when incubated with human liver S-9 fraction and UDPGA. The potential formation of glycerol esters of carboxylic acid drugs undergoing acyl glucuronidation in vitro represents an experimental artifact to which drug metabolism scientists should be aware.

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

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 22 publications

References 1 publication

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

Plasma Stability-Dependent Circulation of Acyl Glucuronide Metabolites in Humans: How Circulating Metabolite Profiles of Muraglitazar and Peliglitazar Can Lead to Misleading Risk Assessment

Glycerolysis of Acyl Glucuronides as an Artifact of in Vitro Drug Metabolism Incubations

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