Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2021 Apr;95(4):1443-1462.
doi: 10.1007/s00204-021-02990-9. Epub 2021 Feb 7.

From street to lab: in vitro hepatotoxicity of buphedrone, butylone and 3,4-DMMC

Rita Roque Bravo  1 , Helena Carmo  2 , Maria João Valente  3 , João Pedro Silva  2 , Félix Carvalho  2 , Maria de Lourdes Bastos  2 , Diana Dias da Silva  4
Affiliations
Comparative Study

From street to lab: in vitro hepatotoxicity of buphedrone, butylone and 3,4-DMMC

Rita Roque Bravo et al. Arch Toxicol. 2021 Apr.

Abstract

Synthetic cathinones are among the most popular new psychoactive substances, being abused for their stimulant properties, which are similar to those of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Considering that the liver is a likely target for cathinones-induced toxicity, and for their metabolic activation/detoxification, we aimed to determine the hepatotoxicity of three commonly abused synthetic cathinones: butylone, α-methylamino-butyrophenone (buphedrone) and 3,4-dimethylmethcathinone (3,4-DMMC). We characterized their cytotoxic profile in primary rat hepatocytes (PRH) and in the HepaRG and HepG2 cell lines. PRH was the most sensitive cell model, showing the lowest EC50 values for all three substances (0.158 mM for 3,4-DMMC; 1.21 mM for butylone; 1.57 mM for buphedrone). Co-exposure of PRH to the synthetic cathinones and CYP450 inhibitors (selective and non-selective) proved that hepatic metabolism reduced the toxicity of buphedrone but increased that of butylone and 3,4-DMMC. All compounds were able to increase oxidative stress, disrupting mitochondrial homeostasis and inducing apoptotic and necrotic features, while also increasing the occurrence of acidic vesicular organelles in PRH, compatible with autophagic activation. In conclusion, butylone, buphedrone and 3,4-DMMC have hepatotoxic potential, and their toxicity lies in the interference with a number of homeostatic processes, while being influenced by their metabolic fate.

Keywords: Apoptosis; Autophagy; CYP2D6; CYP2E1; CYP3A4; Liver toxicity; Necrosis; New psychoactive substances (NPS).

PubMed Disclaimer

References

    1. Adamowicz P, Gieron J, Gil D, Lechowicz W, Skulska A, Tokarczyk B (2016) The prevalence of new psychoactive substances in biological material—a three-year review of casework in Poland. Drug Test Anal 8(1):63–70. https://doi.org/10.1002/dta.1924 - DOI - PubMed
    1. Aninat C, Piton A, Glaise D et al (2006) Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 34(1):75–83. https://doi.org/10.1124/dmd.105.006759 - DOI - PubMed
    1. Araujo AM, Valente MJ, Carvalho M et al (2015) Raising awareness of new psychoactive substances: chemical analysis and in vitro toxicity screening of “legal high” packages containing synthetic cathinones. Arch Toxicol 89(5):757–771. https://doi.org/10.1007/s00204-014-1278-7 - DOI - PubMed
    1. Arbo MD, Silva R, Barbosa DJ et al (2016) In vitro neurotoxicity evaluation of piperazine designer drugs in differentiated human neuroblastoma SH-SY5Y cells. J Appl Toxicol 36(1):121–130. https://doi.org/10.1002/jat.3153 - DOI - PubMed
    1. Astashkina A, Mann B, Grainger DW (2012) A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. Pharmacol Ther 134(1):82–106. https://doi.org/10.1016/j.pharmthera.2012.01.001 - DOI - PubMed

Publication types

MeSH terms

LinkOut - more resources