Metabolic profile of mephedrone: Identification of nor-mephedrone conjugates with dicarboxylic acids as a new type of xenobiotic phase II metabolites

Linhart, Igor; Himl, Michal; Židková, Monika; Balı́ková, Marie; Lhotková, Eva; Páleníček, Tomáš

doi:10.1016/j.toxlet.2015.10.025

Cited by 23 publications

(27 citation statements)

References 24 publications

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“…Linhart et al . (2016) observed a ratio of 3:1 for erythro - and threo - 1-dihydro-normephedrone 34 . This proportion among isomers might also be confirmed in this study by assuming the same eluting profile, although their analytical standards were not available.…”

Section: Resultsmentioning

confidence: 98%

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A new approach towards biomarker selection in estimation of human exposure to chiral chemicals: a case study of mephedrone

Castrignanò

Mardal

Rydevik

et al. 2017

Sci Rep

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Wastewater-based epidemiology is an innovative approach to estimate public health status using biomarker analysis in wastewater. A new compound detected in wastewater can be a potential biomarker of an emerging trend in public health. However, it is currently difficult to select new biomarkers mainly due to limited human metabolism data. This manuscript presents a new framework, which enables the identification and selection of new biomarkers of human exposure to drugs with scarce or unknown human metabolism data. Mephedrone was targeted to elucidate the assessment of biomarkers for emerging drugs of abuse using a four-step analytical procedure. This framework consists of: (i) identification of possible metabolic biomarkers present in wastewater using an in-vivo study; (ii) verification of chiral signature of the target compound; (iii) confirmation of human metabolic residues in in-vivo/vitro studies and (iv) verification of stability of biomarkers in wastewater. Mephedrone was selected as a suitable biomarker due to its high stability profile in wastewater. Its enantiomeric profiling was studied for the first time in biological and environmental matrices, showing stereoselective metabolism of mephedrone in humans. Further biomarker candidates were also proposed for future investigation: 4′-carboxy-mephedrone, 4′-carboxy-normephedrone, 1-dihydro-mephedrone, 1-dihydro-normephedrone and 4′-hydroxy-normephedrone.

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Section: Resultsmentioning

confidence: 98%

“… Legend: a metabolites mentioned in 14 , b those formed in pHLM incubation through set A experiment and c through set B, d those not previously published, e those mentioned in 34 . …”

Section: Resultsmentioning

confidence: 99%

A new approach towards biomarker selection in estimation of human exposure to chiral chemicals: a case study of mephedrone

Castrignanò

Mardal

Rydevik

et al. 2017

Sci Rep

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“…To the best of our knowledge, only one other GNAT enzyme, aminoglycoside 2’- N -acetyltransferase (AAC(2’)-Ic), will accept malonyl-CoA as a substrate [42]. N -Succinoylation, however, has been demonstrated in the detoxification of mammalian xenobiotics [43,44], N -succinoyl conjugates of octopomine, serotonin, dopamine, and tyramine have been identified in C. elegans [45], N -succinoylserotonin (bufobutanoic acid) is found in the venom of various toad species (the traditional Chinese medicine, Ch’an Su ) [46], and crystallographic results identified succinoyl-CoA bound in two GNAT enzymes [47,48]. Our data showing that malonyl-CoA is a Bm -iAANAT3 substrate in combination with these other works hints that a panel of N -malonylated and N -succinoylated amines may exist in both vertebrates and invertebrates.…”

Section: Resultsmentioning

confidence: 99%

Bm-iAANAT3: Expression and characterization of a novel arylalkylamine N-acyltransferase from Bombyx mori

Battistini

O’Flynn

Shoji

et al. 2019

Archives of Biochemistry and Biophysics

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The arylalkylamine N-acyltransferases (AANATs) are enzymes that catalyze the acyl-CoA-dependent formation of N-acylarylalkylamides: acyl-CoA + arylalkylamine → N-acylarylalkylamides + CoA-SH. Herein, we describe our study of a previously uncharacterized AANAT from Bombyx mori: Bm-iAANAT3. Bm-iAANAT3 catalyzes the direct formation of N-acylarylalkylamides and accepts a broad range of short-chain acyl-CoA thioesters and amines as substrates. Acyl-CoA thioesters possessing an acyl chain length >10 carbon atoms are not substrates for Bm-iAANAT3. We report that Bm-iAANAT3 is a “versatile generalist”, most likely, functioning in amine acetylation – a reaction in amine inactivation/excretion, cuticle sclerotization, and melanism. We propose a kinetic and chemical mechanism for Bm-iAANAT3 that is consistent with our steady-state kinetic analysis, dead-end inhibition studies, determination of the pH-rate profiles, and site-directed mutagenesis of a catalytically important amino acid in Bm-iAANAT3. These mechanistic studies of Bm-iAANAT3 will foster the development of novel compounds targeted against this enzyme and other insect AANATs for the control of insect pests.

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“…As described by Niessen and Correa [22], loss of water ( Table S1). In rat urine, conjugates of mephedrone and methylone metabolites with succinic, glutaric, and adipic acid were previously detected [23,24]. Nor-mephedrone succinate was also described to be present in human plasma and urine [25,26].…”

Section: Identification Of Metabolites In Vivo and In Vitromentioning

confidence: 99%

Toxicokinetic studies of the four new psychoactive substances 4-chloroethcathinone, N-ethylnorpentylone, N-ethylhexedrone, and 4-fluoro-alpha-pyrrolidinohexiophenone

et al. 2019

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The presented study aimed to elucidate the toxicokinetics of the four synthetic cathinones 4chloroethcathinone (4-CEC), N-ethylnorpentylone (N-ethylpentylone, ephylone), N-ethylhexedrone (NEH), and 4-fluoro-alpha-pyrrolidinohexiophenone (4-fluoro-alpha-pyrrolidinohexanophenone, 4-F-PHP, 4F-alpha-PHP, 4F-PHP). Methods First, their metabolism was studied using human urine and blood samples. Analysis of specimens was performed by liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS) and gas chromatography-mass spectrometry (GC-MS). LC-HRMS/MS was also used to analyze in vitro incubations of the new psychoactive substances using pooled human liver S9 fraction (pS9), to identify the monooxygenases involved in the initial metabolic steps, and determination of plasma concentrations after standard addition method. Metabolic stability was tested in pooled human liver microsomes incubations analyzed by LC-ion trap MS. Results Using LC-HRMS/MS, in total 47 metabolites were found in patient samples and pS9 incubations. Using GC-MS, 4-CEC, ephylone, NEH, and five of their metabolites were detectable in urine. The following main phase I reactions were observed: carbonyl group reduction, N-deethylation, hydroxylation, lactam formation (4F-PHP), and demethylenation (ephylone). Mainly glucuronidations were observed as phase II reactions besides conjugates with the dicarboxylic acids malonic, succinic, and glutaric acid (4-CEC), sulfation, methylation (both ephylone), and Nacetylation (NEH). A broad range of monooxygenases was involved in the initial steps with exception of NEH (only CYP1A2 and CYP2C19). 4F-PHP had the shortest in vitro half-life (38 min) and highest intrinsic clearance (15.7 mL×min-1 ×kg-1). Plasma concentrations ranged from 0.8 to 8.5 ng/mL. Conclusions Our results are expected to help toxicologists to reliably identify these substances in case of 3 suspected abuse and allow them a thorough risk assessment.

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Metabolic profile of mephedrone: Identification of nor-mephedrone conjugates with dicarboxylic acids as a new type of xenobiotic phase II metabolites

Cited by 23 publications

References 24 publications

A new approach towards biomarker selection in estimation of human exposure to chiral chemicals: a case study of mephedrone

A new approach towards biomarker selection in estimation of human exposure to chiral chemicals: a case study of mephedrone

Bm-iAANAT3: Expression and characterization of a novel arylalkylamine N-acyltransferase from Bombyx mori

Toxicokinetic studies of the four new psychoactive substances 4-chloroethcathinone, N-ethylnorpentylone, N-ethylhexedrone, and 4-fluoro-alpha-pyrrolidinohexiophenone

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