Pyrrolidinyl Synthetic Cathinones α-PHP and 4F-α-PVP Metabolite Profiling Using Human Hepatocyte Incubations

Carlier, Jérémy; Diao, Xingxing; Giorgetti, Raffaele; Busardò, Francesco Paolo; Huestis, Marilyn A.

doi:10.3390/ijms22010230

Cited by 13 publications

(8 citation statements)

References 46 publications

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“…It has also been reported that 19 phase I metabolites and 9 glucuronide conjugates of α-PHP were identified in human urine of a drug abuser. Among these, β-keto-reduced alcoholic dihydro metabolite and glucuronidated ß-keto-reduced alcohols were the most represented and a recent study has identified α-PHP dihydroxy-pyrrolidinyl as additional major metabolite [36][37][38]. Differently, although its synthetic pathways have been recently investigated, mexedrone pharmacokinetic profile is still unclear [28].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Cytotoxic and Mutagenic Effects of the Synthetic Cathinones Mexedrone, α-PVP and α-PHP

Lenzi

Cocchi

Gasperini

et al. 2021

IJMS

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Mexedrone, α-PVP and α-PHP are synthetic cathinones. They can be considered amphetamine-like substances with a stimulating effect. Actually, studies showing their impact on DNA are totally absent. Therefore, in order to fill this gap, aim of the present work was to evaluate their mutagenicity on TK6 cells. On the basis of cytotoxicity and cytostasis results, we selected the concentrations (35–100 µM) to be used in the further analysis. We used the micronucleus (MN) as indicator of genetic damage and analyzed the MNi frequency fold increase by flow cytometry. Mexedrone demonstrated its mutagenic potential contrary to the other two compounds; we then proceeded by repeating the analyzes in the presence of extrinsic metabolic activation in order to check if it was possible to totally exclude the mutagenic capacity for α-PVP and α-PHP. The results demonstrated instead the mutagenicity of their metabolites. We then evaluated reactive oxygen species (ROS) induction as a possible mechanism at the basis of the highlighted effects but the results did not show a statistically significant increase in ROS levels for any of the tested substances. Anyway, our outcomes emphasize the importance of mutagenicity evaluation for a complete assessment of the risk associated with synthetic cathinones exposure.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Cytotoxic and Mutagenic Effects of the Synthetic Cathinones Mexedrone, α-PVP and α-PHP

Lenzi

Cocchi

Gasperini

et al. 2021

IJMS

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“…αPHP, a less common analogue of αPVP, is a one of the pyrovalerone derivatives (-pyrrolidinophenones) known to be a SCs subgroup chemically characterized by a pyrrolidine ring and a long side chain linked to the -carbon [ 18 , 19 ]. The first report on αPHP identification occurred in 2014 in Japan [ 17 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

The Designer Drug αPHP Affected Cell Proliferation and Triggered Deathly Mechanisms in Murine Neural Stem/Progenitor Cells

Roda,

De Luca,

Priori

et al. 2023

Biology

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Increasing reports of neurological and psychiatric outcomes due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the understanding of neurotoxic mechanisms is still lacking, particularly for the under-investigated αPHP, one of the major MDPV derivatives. In particular, its effects on neural stem/progenitor cell cultures (NSPCs) are still unexplored. Therefore, in the current in vitro study, the effects of increasing αPHP concentrations (25–2000 μM), on cell viability/proliferation, morphology/ultrastructure, genotoxicity and cell death pathways, have been evaluated after exposure in murine NSPCs, using a battery of complementary techniques, i.e., MTT and clonogenic assay, flow cytometry, immunocytochemistry, TEM, and patch clamp. We revealed that αPHP was able to induce a dose-dependent significant decrease of the viability, proliferation and clonal capability of the NSPCs, paralleled by the resting membrane potential depolarization and apoptotic/autophagic/necroptotic pathway activation. Moreover, ultrastructural alterations were clearly observed. Overall, our current findings demonstrate that αPHP, damaging NSPCs and the morpho-functional fundamental units of adult neurogenic niches may affect neurogenesis, possibly triggering long-lasting, irreversible CNS damage. The present investigation could pave the way for a broadened understanding of SCs toxicology, needed to establish an appropriate treatment for NPS and the potential consequences for public health.

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“…To identify the most relevant biomarkers of α-MT consumption in clinical and forensic caseworks, we assessed α-MT human metabolism with: (1) in silico metabolite predictions to assist sample analysis and data mining, (2) in vitro incubations with primary human hepatocytes to simulate phase I and phase II metabolism in conditions similar to in vivo [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], and (3) the analysis of postmortem samples from an authentic overdose death to verify the in vitro results. Incubates and samples were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) in positive- and negative-ionization modes and software-assisted data mining for an all-inclusive screening of α-MT metabolites.…”

Section: Introductionmentioning

confidence: 99%

α-Methyltryptamine (α-MT) Metabolite Profiling in Human Hepatocyte Incubations and Postmortem Urine and Blood

Malaca

Bottinelli²,

Fanton

et al. 2023

Metabolites

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α-MT is a hallucinogenic and stimulant tryptamine that was involved in several overdose fatalities in the United States and Europe. Analytical toxicology, and particularly the identification of metabolite biomarkers in biological samples, often is the only way to prove tryptamine use in clinical and forensic caseworks. We aimed to identify optimal α-MT metabolite biomarkers of consumption in humans. We identified α-MT metabolites in 10-donor-pooled human hepatocyte incubations and postmortem urine and blood from an α-MT overdose case using in silico metabolite predictions, liquid chromatography high-resolution-tandem mass spectrometry (LC-HRMS/MS), and software-assisted data mining. Nine metabolites were identified in vitro and eight additional metabolites were found in urine; five metabolites were found in blood. Metabolic transformations were hydroxylation, O-sulfation, O-glucuronidation, N-glucuronidation, and N-acetylation, consistent with the metabolism of structural analogues. The findings in hepatocyte incubations and postmortem samples were consistent, proving the in vitro model suitability. We suggest α-MT, hydroxy-α-MT glucuronide, and two hydroxy-α-MT sulfates as biomarkers of α-MT use in non-hydrolyzed urine; we suggest α-MT, two hydroxy-α-MT sulfates and N-acetyl-α-MT as biomarkers of α-MT use in blood. Further studies on α-MT clinical and forensic caseworks with different doses and routes of administration are necessary to better explore α-MT metabolism.

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Pyrrolidinyl Synthetic Cathinones α-PHP and 4F-α-PVP Metabolite Profiling Using Human Hepatocyte Incubations

Cited by 13 publications

References 46 publications

Evaluation of Cytotoxic and Mutagenic Effects of the Synthetic Cathinones Mexedrone, α-PVP and α-PHP

Evaluation of Cytotoxic and Mutagenic Effects of the Synthetic Cathinones Mexedrone, α-PVP and α-PHP

The Designer Drug αPHP Affected Cell Proliferation and Triggered Deathly Mechanisms in Murine Neural Stem/Progenitor Cells

α-Methyltryptamine (α-MT) Metabolite Profiling in Human Hepatocyte Incubations and Postmortem Urine and Blood

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