Characterization of a novel diclofenac metabolite in human urine by capillary gas chromatography-negative chemical ionization mass spectrometry

Blum, W.; Faigle, J. W.; Pfaar, Ulrike; Sallmann, A

doi:10.1016/s0378-4347(96)00198-3

Cited by 31 publications

(14 citation statements)

References 24 publications

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“…At the end of 112 d of incubation, 5HD was detected in all soils, while 24DCB and 26DCB were found in Irvine soil, 24DCB and 3,5-dichlorobenzoic acid (35DCB) in Maricopa soil, and 24DCB in Ventura soil. It is likely that oxidation of DCL led to the formation of 5HD, and both DCL and 5HD may serve as precursors to DCB through N -dealkylation of the biphenyl compounds followed by carboxylation (Figure 5) (Blum et al, 1996; Pérez and Barceló, 2008). 4′-Hydroxydiclofenac was analyzed for, but not detected in any sample, in contrast to other observations made using microbial culture or human metabolic enzymes (Bort et al, 1999; Webster et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

Transformation and removal pathways of four common PPCP/EDCs in soil

Dodgen

et al. 2014

Environmental Pollution

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Pharmaceutical and personal care products (PPCPs) and endocrine disrupting chemicals (EDCs) enter the soil environment via irrigation with treated wastewater, groundwater recharge, and land application of biosolids. The transformation and fate of PPCP/EDCs in soil affects their potential for plant uptake and groundwater pollution. This study examined four PPCP/EDCs (bisphenol A, diclofenac, naproxen, and 4-nonylphenol) in soil by using 14C-labeling and analyzing mineralization, extractable residue, bound residue, and formation of transformation products. At the end of 112 d of incubation, the majority of 14C-naproxen and 14C-diclofenac was mineralized to 14CO2, while a majority of 14C-bisphenol A and 14C-nonylphenol was converted to bound residue. After 112 d, the estimated half-lives of the parent compounds were only 1.4 – 5.4 d. However a variety of transformation products were found and several for bisphenol A and diclofenac were identified, suggesting the need to consider degradation intermediates in soils impacted by PPCP/EDCs.

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Section: Resultsmentioning

confidence: 99%

Transformation and removal pathways of four common PPCP/EDCs in soil

Dodgen

et al. 2014

Environmental Pollution

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“…First, DCF undergoes ring hydroxylation, catalyzed by cytochrome P450 (CYP) isoenzyme CYP2C9, resulting in the formation of the major oxidative metabolite, 4 0 -OH-DCF (Stierlin and Faigle 1979). Other, quantitatively minor products of oxidative metabolism include 5-OH-DCF, catalyzed by CYP3A4 (Shen et al 1999;Tang et al 1999), as well as a number of other mono-or di-hydroxylated metabolites (Blum et al 1996;Bort et al 1999). Both the 4 0 -OH-DCF and 5-OH-DCF can be further oxidized into quinone imines.…”

Section: Metabolites Of Fungal Dcf Transformationmentioning

confidence: 99%

Removal of diclofenac and mefenamic acid by the white rot fungus Phanerochaete sordida YK-624 and identification of their metabolites after fungal transformation

et al. 2010

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The non-steroidal anti-inflammatory drugs diclofenac (DCF) and mefenamic acid (MFA) were treated with the white rot fungus Phanerochaete sordida YK-624. DCF completely disappeared and MFA decreased by about 90% after 6 days of treatment. It was also confirmed that the fungus almost completely removed the acute lethal toxicity of DCF and MFA towards the freshwater crustacean Thamnocephalus platyurus after 6 days of treatment. Mass spectrometric and (1)H nuclear magnetic resonance analyses demonstrated that two mono-hydroxylated DCFs (4'-hydroxydiclofenac and 5-hydroxydiclofenac) and one di-hydroxylated DCF (4',5-dihydroxydiclofenac) were formed via fungal transformation. The four metabolites of MFA were identified as 3'-hydroxymethylmefenamic acid (mono-hydroxylated MFA), 3'-hydroxymethyl-5-hydroxymefenamic acid (di-hydroxylated MFA), 3'-hydroxymethyl-6'-hydroxymefenamic acid (di-hydroxylated MFA) and 3'-carboxymefenamic acid. These results suggest that hydroxylation catalyzed by cytochrome P450 (CYP) in P. sordida YK-624 may be involved in the elimination and detoxification of DCF and MFA. This notion was further supported by the fact that smaller decreases in DCF and MFA were observed in cultures of P. sordida YK-624 incubated with 1-aminobenzotriazole, a known inhibitor of CYP.

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“…Although the exact mechanism leading to formation of arene oxides has not been completely understood yet, many kinetic and theoretical studies of benzene hydroxylation by P450 enzymes support a model in which a cationic -complex (or radical -complex) is first produced, prior to the formation of arene oxides (Ortiz de Montellano, 1995;de Visser and Shaik, 2003). Because diclofenac-3Ј,4Ј-oxide has previously been proposed to be the precursor molecule of 4Ј-hydroxydiclofenac (Blum et al, 1996), formation of which was mediated specifically by CYP2C9 (Leemann et al, 1993), we hypothesized that both diclofenac-3Ј,4Ј-oxide and diclofenac-2Ј,3Ј-oxide are formed via a common intermediate. As depicted in Scheme 4, oxidation at the 3Ј-C position of diclofenac generates a cationic -complex (or radical -complex) that subsequently forms two isomeric oxides, diclofenac-3Ј,4Ј-oxide and diclofenac-2Ј,3Ј-oxide.…”

Section: Yan Et Almentioning

confidence: 99%

Detection of a Novel Reactive Metabolite of Diclofenac: Evidence for Cyp2c9-Mediated Bioactivation via Arene Oxides

Yan

Li²,

Huebert³

et al. 2005

Drug Metab Dispos

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ABSTRACT:A new glutathione adduct (M4) was tentatively identified, likely as 2-hydroxy-3-(glutathione-S-yl)-monoclofenac, using liquid chromatography-tandem mass spectrometry analysis of incubations of diclofenac with human liver microsomes. The same conjugate was not detected in incubations with either rat or monkey liver microsomes. Formation of M4 was mediated specifically by CYP2C9 in human liver microsomes, as evidenced by the following observations: 1) cDNA-expressed CYP2C9-catalyzing formation of M4; 2) inhibition of M4 formation by sulfaphenazole, a CYP2C9-selective inhibitor; and 3) strong correlation between the production of M4 and CYP2C9-mediated tolbutamide 4-hydroxylase activities in a panel of human liver microsome samples. Formation of M4 suggests the existence of a new reactive intermediate as diclofenac-2,3-oxide. A tentative pathway states that diclofenac is oxidized to diclofenac-2,3-oxide that reacts with glutathione (GSH) to form a thioether conjugate at the C-3 position, followed by a concomitant loss of chlorine to give rise to M4. Furthermore, a likely mechanism leading to the formation of diclofenac oxides is rationalized: CYP2C9-catalyzed oxidation at the C-3 position of the dichlorophenyl ring to form a cationic -complex that subsequently results in diclofenac-3,4-oxide and diclofenac-2,3-oxide; the former oxide is converted to 4-hydroxy-diclofenac as a major metabolite and can be trapped by GSH to produce 4-hydroxy-3-glutathione-S-yl diclofenac (M2), whereas the latter oxide forms 3-hydroxy-diclofenac and can be trapped by GSH to produce M4. This mechanism is consistent with the structural modeling of the CYP2C9-diclofenac complex, which reveals that both the C-3 and C-4 of the dichlorophenyl ring are proximate to the heme group.

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Characterization of a novel diclofenac metabolite in human urine by capillary gas chromatography-negative chemical ionization mass spectrometry

Cited by 31 publications

References 24 publications

Transformation and removal pathways of four common PPCP/EDCs in soil

Transformation and removal pathways of four common PPCP/EDCs in soil

Removal of diclofenac and mefenamic acid by the white rot fungus Phanerochaete sordida YK-624 and identification of their metabolites after fungal transformation

Detection of a Novel Reactive Metabolite of Diclofenac: Evidence for Cyp2c9-Mediated Bioactivation via Arene Oxides

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