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Bioactivation of glafenine by human liver microsomes and peroxidases: identification of electrophilic iminoquinone species and GSH conjugates.
Drug Metab Dispos. 2011 Sep; 39(9):1511-21.DM

Abstract

Glafenine (Privadol; 2,3-dihydroxypropyl 2-[(7-chloro-4-quinolinyl) amino]benzoate) is a non-narcotic analgesic agent widely used for the treatment of pains of various origins. Severe liver toxicity and a high incidence of anaphylaxis were reported in patients treated with glafenine, eventually leading to its withdrawal from the market in most countries. It is proposed that bioactivation of glafenine and subsequent binding of reactive metabolite(s) to critical cellular proteins play a causative role. The study described herein aimed at characterizing pathways of glafenine bioactivation and the metabolic enzymes involved. Two GSH conjugates of glafenine were detected in human liver microsomal incubations using liquid chromatography tandem mass spectrometry. The structures of detected conjugates were determined as GSH adducts of 5-hydroxyglafenine (M3) and 5-hydroxy glafenic acid (M4), respectively. GSH conjugation took place with a strong preference at C6 of the benzene ring of glafenine, ortho to the carbonyl moiety. These findings are consistent with a bioactivation sequence involving initial cytochrome P450-catalyzed 5-hydroxylation of the benzene ring of glafenine, followed by two electron oxidations of M3 and M4 to form corresponding para-quinone imine intermediates that react with GSH to form GSH adducts M1 and M2, respectively. Formation of M1 and M2 was primarily catalyzed by heterologously expressed recombinant CYP3A4 and to a lesser extent, CYP2C19 and CYP2D6. We demonstrated that M3 can also be bioactivated by peroxidases, such as horseradish peroxidase and myeloperoxidase. In summary, these findings have significance in understanding the bioactivation pathways of glafenine and their potential link to mechanisms of toxicity of glafenine.

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Authors+Show Affiliations

Wen B
Drug Metabolism, eADME, Non-Clinical Safety, Hoffmann-La Roche, Inc., 340 Kingsland Street, 123/1341, Nutley, NJ 07110, USA. bo.wen@roche.com
Moore DJ
No affiliation info available

MeSH

CyclophilinsCytochrome P-450 Enzyme SystemGlafenineGlutathioneHumansInactivation, MetabolicMicrosomes, LiverOxidation-ReductionPeroxidasesProtein BindingQuinonesTandem Mass Spectrometry

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21628497

Citation

Wen, Bo, and David J. Moore. "Bioactivation of Glafenine By Human Liver Microsomes and Peroxidases: Identification of Electrophilic Iminoquinone Species and GSH Conjugates." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 39, no. 9, 2011, pp. 1511-21.
Wen B, Moore DJ. Bioactivation of glafenine by human liver microsomes and peroxidases: identification of electrophilic iminoquinone species and GSH conjugates. Drug Metab Dispos. 2011;39(9):1511-21.
Wen, B., & Moore, D. J. (2011). Bioactivation of glafenine by human liver microsomes and peroxidases: identification of electrophilic iminoquinone species and GSH conjugates. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 39(9), 1511-21. https://doi.org/10.1124/dmd.111.039396
Wen B, Moore DJ. Bioactivation of Glafenine By Human Liver Microsomes and Peroxidases: Identification of Electrophilic Iminoquinone Species and GSH Conjugates. Drug Metab Dispos. 2011;39(9):1511-21. PubMed PMID: 21628497.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bioactivation of glafenine by human liver microsomes and peroxidases: identification of electrophilic iminoquinone species and GSH conjugates. AU - Wen,Bo, AU - Moore,David J, Y1 - 2011/05/31/ PY - 2011/6/2/entrez PY - 2011/6/2/pubmed PY - 2012/3/1/medline SP - 1511 EP - 21 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 39 IS - 9 N2 - Glafenine (Privadol; 2,3-dihydroxypropyl 2-[(7-chloro-4-quinolinyl) amino]benzoate) is a non-narcotic analgesic agent widely used for the treatment of pains of various origins. Severe liver toxicity and a high incidence of anaphylaxis were reported in patients treated with glafenine, eventually leading to its withdrawal from the market in most countries. It is proposed that bioactivation of glafenine and subsequent binding of reactive metabolite(s) to critical cellular proteins play a causative role. The study described herein aimed at characterizing pathways of glafenine bioactivation and the metabolic enzymes involved. Two GSH conjugates of glafenine were detected in human liver microsomal incubations using liquid chromatography tandem mass spectrometry. The structures of detected conjugates were determined as GSH adducts of 5-hydroxyglafenine (M3) and 5-hydroxy glafenic acid (M4), respectively. GSH conjugation took place with a strong preference at C6 of the benzene ring of glafenine, ortho to the carbonyl moiety. These findings are consistent with a bioactivation sequence involving initial cytochrome P450-catalyzed 5-hydroxylation of the benzene ring of glafenine, followed by two electron oxidations of M3 and M4 to form corresponding para-quinone imine intermediates that react with GSH to form GSH adducts M1 and M2, respectively. Formation of M1 and M2 was primarily catalyzed by heterologously expressed recombinant CYP3A4 and to a lesser extent, CYP2C19 and CYP2D6. We demonstrated that M3 can also be bioactivated by peroxidases, such as horseradish peroxidase and myeloperoxidase. In summary, these findings have significance in understanding the bioactivation pathways of glafenine and their potential link to mechanisms of toxicity of glafenine. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/21628497/Bioactivation_of_glafenine_by_human_liver_microsomes_and_peroxidases:_identification_of_electrophilic_iminoquinone_species_and_GSH_conjugates_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21628497 DB - PRIME DP - Unbound Medicine ER -