Simultaneous Detection of Cholyl Adenylate and Coenzyme A Thioester Utilizing Liquid Chromatography/Electrospray Ionization Mass Spectrometry

Mano, Nariyasu; Uchida, Masashi; Okuyama, Hiroko; Sasaki, Ikuko; Ikegawa, Shigeo; Goto, Junichi

doi:10.2116/analsci.17.1037

Cited by 23 publications

(11 citation statements)

References 29 publications

(13 reference statements)

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“…Concentration-dependent experiments were performed with increasing concentrations of (R)-(-)-ibuprofen or (S)-(+)-ibuprofen (2,4,8,16,32,63,125,250, 500, and 1000 µM) incubated with rat hepatocytes (2 × 10 6 cells/mL) for an incubation time of 3 min.…”

Section: Methodsmentioning

confidence: 99%

Enantioselective Formation of Ibuprofen-S-Acyl-Glutathione in Vitro in Incubations of Ibuprofen with Rat Hepatocytes

Grillo

Hua

2008

Chem. Res. Toxicol.

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Ibuprofen is metabolized to chemically reactive ibuprofen-1- O-acyl-glucuronide (I-1- O-G) and ibuprofen- S-acyl-CoA (I-CoA) derivatives, which are proposed to mediate the formation of drug-protein adducts via the transacylation of protein nucleophiles. We examined the ability of ibuprofen to undergo enantioselective metabolism to ibuprofen- S-acyl-glutathione thioester (I-SG) in incubations with rat hepatocytes, where I-CoA formation is known to be highly enantioselective in favor of the (R)-(-)-ibuprofen isomer. We proposed that potential enantioselective transacylation of glutathione forming I-SG in favor of the (R)-(-)-isomer would reveal the importance of acyl-CoA formation, versus acyl glucuronidation, in the generation of reactive transacylating-type intermediates of the drug. Thus, when (R)-(-)- and (S)-(+)-ibuprofen (100 microM) were incubated with hepatocytes, the presence of I-CoA and I-SG was detected in incubation extracts by LC-MS/MS techniques. The formation of I-CoA and I-SG in hepatocyte incubations with (R)-(-)-ibuprofen was rapid and reached maximum concentrations of 2.6 microM and 1.3 nM, respectively, after 8-10 min of incubation. By contrast, incubations with (S)-(+)-ibuprofen resulted in 8% and 3.9% as much I-CoA and I-SG formation, respectively, compared to that in corresponding incubations with the (R)-(-)-isomer. Experiments with a pseudoracemic mixture of (R)-(-)-[3,3,3-(2)H3]- and (S)-(+)-ibuprofen showed that >99% of the I-SG detected in hepatocyte incubations contained deuterium and therefore was derived primarily from (R)-(-)-ibuprofen bioactivation. Inhibition of (R)-(-)-ibuprofen (10 microM) glucuronidation with (-)-borneol (100 microM) led to a 98% decrease in I-1-O-G formation; however, no decrease in I-SG production was observed. Coincubation with pivalic, valproic, or lauric acid (500 microM each) was shown to lead to a significant inhibition of I-CoA formation and a corresponding decrease in I-SG production. Results from these studies demonstrate that the reactive I-CoA derivative, and not the I-1-O-G metabolite, plays a central role in the transacylation of GSH in incubations with rat hepatocytes.

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Section: Methodsmentioning

confidence: 99%

Enantioselective Formation of Ibuprofen-S-Acyl-Glutathione in Vitro in Incubations of Ibuprofen with Rat Hepatocytes

Grillo

Hua

2008

Chem. Res. Toxicol.

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“…In addition to being adaptable for the analysis of fatty acylCoAs with acyl chains longer or shorter than those described here (and stable isotope-labeled fatty acids for kinetic studies) (5), the neutral loss (507.0 Da) scan should be able to detect and analyze CoA thioesters with other compounds, such as bile acids (36) and certain xenobiotics (8).…”

Section: Quantitation Of Fatty Acyl-coas By Lc-ms/msmentioning

confidence: 99%

Quantitation of fatty acyl-coenzyme As in mammalian cells by liquid chromatography-electrospray ionization tandem mass spectrometry

Haynes

Allegood

Sims

et al. 2008

Journal of Lipid Research

104

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“…MFA is also metabolized into the reactive MFA-acyl-adenylate (MFA-AMP) and MFA-S-acyl-coenzyme A (MFA-CoA) via acyl-CoA synthetase (ACS), both of which have been demonstrated to form L-glutathione (GSH)-adducts and are proposed to play a role in MFA-mediated idiosyncratic toxicity (Grillo et al, 2012;Horng and Benet, 2013). This pathway occurs when the AMP moiety of ATP is covalently transferred to the carboxyl group of MFA to form MFA-AMP, followed by the displacement of the AMP with coenzyme A (CoA) to form MFA-CoA thioesters (Kelley and Vessey, 1994;Mano et al, 2001). Upon their formation, the carbonyl carbons of both MFA-AMP and MFA-CoA increase in electrophilicity, enabling them to transacylate the biologic nucleophile GSH (Horng and Benet, 2013).…”

Section: Introductionmentioning

confidence: 99%

The Nonenzymatic Reactivity of the Acyl-Linked Metabolites of Mefenamic Acid toward Amino and Thiol Functional Group Bionucleophiles

Horng¹,

Benet²

2013

Drug Metab Dispos

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Mefenamic acid (MFA), a carboxylic acid-containing nonsteroidal anti-inflammatory drug, is metabolized into the chemically-reactive MFA-1-O-acyl-glucuronide (MFA-1-O-G), MFA-acyl-adenylate (MFA-AMP), and the MFA-S-acyl-coenzyme A (MFA-CoA), all of which are electrophilic and capable of acylating nucleophilic sites on biomolecules. In this study, we investigate the nonenzymatic ability of each MFA acyl-linked metabolite to transacylate amino and thiol functional groups on the acceptor biomolecules Gly, Tau,

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Simultaneous Detection of Cholyl Adenylate and Coenzyme A Thioester Utilizing Liquid Chromatography/Electrospray Ionization Mass Spectrometry

Cited by 23 publications

References 29 publications

Enantioselective Formation of Ibuprofen-S-Acyl-Glutathione in Vitro in Incubations of Ibuprofen with Rat Hepatocytes

Enantioselective Formation of Ibuprofen-S-Acyl-Glutathione in Vitro in Incubations of Ibuprofen with Rat Hepatocytes

Quantitation of fatty acyl-coenzyme As in mammalian cells by liquid chromatography-electrospray ionization tandem mass spectrometry

The Nonenzymatic Reactivity of the Acyl-Linked Metabolites of Mefenamic Acid toward Amino and Thiol Functional Group Bionucleophiles

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