Is the formation of R-ibuprofenyl-adenylate the first stereoselective step of chiral inversion?

Menzel, S.; Waibel, Reiner; Brune, Kay; Geißlinger, Gerd

doi:10.1016/0006-2952(94)90380-8

Cited by 43 publications

(26 citation statements)

References 11 publications

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“…Potentially, metabolism of MFA by acyl-CoA synthetase(s) leads to a buildup of an intermediate MFA-acyl-adenylate. Xenobiotic and endogenous carboxylic acids have been shown to be converted to chemically reactive mixed anhydride adenosine 5-monophosphate-linked intermediates detected during the formation of their corresponding S-acyl-CoA thioesters (Mao et al, 1992;Hall and Quan, 1994;Menzel et al, 1994;Ikegawa et al, 1999). Acyl-adenylate intermediates of endogenous bile acids, such as cholic acid (Ikegawa et al, 1999), are known to be reactive acylating derivatives that undergo transacylation-type reactions with the amino group of taurine, with peptides and proteins, and with the thiol group of GSH, leading to the formation of bile acid S-acyl-GSH conjugates (Goto et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Activation of Mefenamic Acid Leading to Mefenamyl-S-Acyl-Glutathione Adduct Formation In Vitro and In Vivo in Rat

Grillo

Lohr²,

Wait³

2012

Drug Metab Dispos

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ABSTRACT:Carboxylic acid-containing nonsteroidal anti-inflammatory drugs (NSAIDs) can be metabolized to chemically reactive acyl glucuronide and/or S-acyl-CoA thioester metabolites capable of transacylating GSH. We investigated the metabolism of the NSAID mefenamic acid (MFA) to metabolites that transacylate GSH, leading to MFA-S-acyl-GSH thioester (MFA-SG) formation in incubations with rat and human hepatocytes and in vivo in rat bile. Thus, incubation of MFA (1-500 M) with rat hepatocytes led to the detection of MFA-1-␤-O-acyl glucuronide (MFA-1-␤-O-G), MFA-S-acylCoA (MFA-SCoA), and MFA-SG by liquid chromatography-tandem mass spectrometric analysis. The C max of MFA-SG (330 nM; 10-min incubation with 100 M MFA) was 120-to 1400-fold higher than the C max of drug S-acyl-GSH adducts detected from studies with other carboxylic acid drugs to date. MFA-SG was also detected in incubations with human hepatocytes, but at much lower concentrations. Inhibition of MFA acyl glucuronidation in rat hepatocytes had no effect on MFA-SG formation, whereas a 58 ؎ 1.7% inhibition of MFA-SCoA formation led to a corresponding 66 ؎ 3.5% inhibition of MFA-SG production. Reactivity comparisons with GSH in buffer showed MFA-SCoA to be 80-fold more reactive than MFA-1-␤-O-G forming MFA-SG. MFA-SG was detected in MFAdosed (100 mg/kg) rat bile, where 17.4 g was excreted after administration. In summary, MFA exhibited bioactivation in rat and human hepatocytes and in vivo in rat, leading to reactive acylating derivatives that transacylate GSH. The formation of MFA-SG in hepatocytes was shown not to be mediated by reaction with MFA-1-␤-O-G, and not solely by MFA-SCoA, but perhaps also by intermediary MFA-acyladenylate formation, which is currently under investigation.

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Section: Discussionmentioning

confidence: 99%

Metabolic Activation of Mefenamic Acid Leading to Mefenamyl-S-Acyl-Glutathione Adduct Formation In Vitro and In Vivo in Rat

Grillo

Lohr²,

Wait³

2012

Drug Metab Dispos

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“…The thioesterification of (Ϫ)-(R)-IBU ( Fig. 1A) with CoA (11) via an adenylate intermediate (12) is catalyzed by a microsomal and mitochondrial enzyme, which we recently characterized as long-chain acylCoA synthetase (13). The unidirectional formation of the respective adenylates with (Ϫ)-R-enantiomers is the stereoselective step of inversion.…”

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confidence: 99%

Molecular Cloning and Expression of a 2-Arylpropionyl-Coenzyme A Epimerase: A Key Enzyme in the Inversion Metabolism of Ibuprofen

et al. 1997

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SUMMARYThe 2-arylpropionic acid derivatives, including ibuprofen, are the most widely used anti-inflammatory analgesic cyclooxygenase inhibitors. The (Ϫ)-R-enantiomer, which is inactive in terms of cyclooxygenase inhibition, is epimerized in vivo via the 2-arylpropionyl-coenzyme A (CoA) epimerase to the cyclooxygenase-inhibiting (ϩ)-S-enantiomer. The molecular biology of the epimerization pathway is largely unknown. To clarify this mechanism, the sequence of the 2-arylpropionyl-CoA epimerase was identified, and the enzyme cloned and expressed. A cDNA clone encoding the 2-arylpropionyl-CoA epimerase was isolated from a rat liver cDNA library. The nucleotide and the deduced amino acid sequence of this enzyme was determined. Significant amino acid sequence similarity was found between the rat epimerase and carnitine dehydratases from Caenorhabditis elegans (41%) and Escherichia coli (27%). A bacterial expression system (E. coli strain M15[pREP4]) was used to express the epimerase protein, representing up to 20 -30% of the total cellular E. coli protein. The expression of the epimerase was confirmed with Western blots using specific antiepimerase antibodies and by measuring the rate of inversion of (R)-ibuprofenoyl-CoA. Northern blot analysis revealed a prominent 1.9-kb mRNA transcript in different rat tissues. In addition to its obvious importance in drug metabolism, the homology of the epimerase with carnitine dehydratases from several species suggests that this protein, which up to now has only been characterized as having a role in drug transformation, has a function in lipid metabolism.

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“…22) Three kinds of enzymes, LACS, epimerase and hydrolase were necessary for the chiral inversion of 2-APAs, 23) and the LACS was considered to be the stereoselective and rate-controlling enzyme. 19) Entailing long incubation times to acquire substantial inversion in the present study and in the research conducted in HEP G2 cell lines 22) suggested that the involved enzymes expressed (or active) in the immortal cell lines were much lower than that of the freshly prepared or in vivo cells. The LACS responsible for the palmitic acid metabolism was identified in Caco-2 cells and its activity was determined to be about 5.5 nmol/min/mg protein (formation of palmitoylCoA) on four days after confluence.…”

Section: Discussionmentioning

confidence: 50%

“…Regardless of whether administration was performed using racemic ibuprofen or the R enantiomer, substantial inversion of the R enantiomer to its antipode was demonstrated, whereas no inversion of S to R enantiomer was observed, consistent with the previous researches. 19,21) Since the inversion of 2-arylpropionic acids was both species and substrates dependent, the development and establishment of human-resourced researching model is of particular importance. To date, only one report provided direct evidence of intestinal inversion of ibuprofen in humans.…”

Section: Discussionmentioning

confidence: 99%

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Unidirectional Inversion of Ibuprofen in Caco-2 Cells: Developing a Suitable Model for Presystemic Chiral Inversion Study

Hao

Wang

Ding

et al. 2005

Biological & Pharmaceutical Bulletin

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Is the formation of R-ibuprofenyl-adenylate the first stereoselective step of chiral inversion?

Cited by 43 publications

References 11 publications

Metabolic Activation of Mefenamic Acid Leading to Mefenamyl-S-Acyl-Glutathione Adduct Formation In Vitro and In Vivo in Rat

Metabolic Activation of Mefenamic Acid Leading to Mefenamyl-S-Acyl-Glutathione Adduct Formation In Vitro and In Vivo in Rat

Molecular Cloning and Expression of a 2-Arylpropionyl-Coenzyme A Epimerase: A Key Enzyme in the Inversion Metabolism of Ibuprofen

Unidirectional Inversion of Ibuprofen in Caco-2 Cells: Developing a Suitable Model for Presystemic Chiral Inversion Study

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