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Hepatotoxicity of piperazine designer drugs: up-regulation of key enzymes of cholesterol and lipid biosynthesis

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Abstract

The piperazine derivatives most frequently consumed for recreational purposes are 1-benzylpiperazine, 1-(3,4-methylenedioxybenzyl) piperazine, 1-(3-trifluoromethylphenyl) piperazine and 1-(4-methoxyphenyl) piperazine. Generally, they are consumed as capsules, tablets or pills but also in powder or liquid forms. Currently, the precise mechanism by which piperazine designer drugs induce hepatotoxicity and whether they act by a common pathway is unclear. To answer this question, we performed a gene array study with rat hepatocytes incubated with the four designer drugs. Non-cytotoxic concentrations were chosen that neither induce a decrease in reduced glutathione or ATP depletion. Analysis of the gene array data showed a large overlap of gene expression alterations induced by the four drugs. This ‘piperazine designer drug consensus signature’ included 101 up-regulated and 309 down-regulated probe sets (p < 0.05; FDR adjusted). In the up-regulated genes, GO groups of cholesterol biosynthesis represented a dominant overrepresented motif. Key enzymes of cholesterol biosynthesis up-regulated by all four piperazine drugs include sterol C4-methyloxidase, isopentyl-diphosphate-Δ-isomerase, Cyp51A1, squalene epoxidase and farnesyl diphosphate synthase. Additionally, glycoprotein transmembrane nmb, which participates in cell adhesion processes, and fatty acid desaturase 1, an enzyme that regulates unsaturation of fatty acids, were also up-regulated by the four piperazine designer drugs. Regarding the down-regulated probe sets, only one gene was common to all four piperazine derivatives, the betaine-homocysteine-S-methyltransferase 2. Analysis of transcription factor binding sites of the ‘piperazine designer drug consensus signature’ identified the sterol regulatory element binding protein (SREBP-1) as strongly overrepresented in the up-regulated genes. SREBP transcription factors are known to regulate multiple genes of cholesterol metabolism. In conclusion, the present study shows that piperazine designer drugs act by up-regulating key enzymes of cholesterol biosynthesis which is likely to increase the risk of phospholipidosis and steatosis.

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Acknowledgments

This study was supported by the SEURAT-1 EU project DETECTIVE and the BMBF projects LivSys and Lebersimulator. Marcelo Dutra Arbo is the recipient of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES Foundation—Brazil) fellowship (Proc. BEX 0593/10-9).

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Authors and Affiliations

  1. UCIBIO/REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 4050-313, Porto, Portugal

    Marcelo Dutra Arbo, Maria de Lourdes Bastos & Helena Carmo

  2. Leibniz Research Centre for Working Environment and Human Factors (IFADO), Technical University of Dortmund, 44139, Dortmund, Germany

    Simone Melega, Regina Stöber, Markus Schug, Patricio Godoy, Raymond Reif, Cristina Cadenas & Jan G. Hengstler

  3. Department of Statistics, Technical University of Dortmund, 44221, Dortmund, Germany

    Eugen Rempel & Jörg Rahnenführer

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Corresponding author

Correspondence to Marcelo Dutra Arbo.

Additional information

Maria de Lourdes Bastos, Helena Carmo and Jan G. Hengstler shared senior authorship.

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Arbo, M.D., Melega, S., Stöber, R. et al. Hepatotoxicity of piperazine designer drugs: up-regulation of key enzymes of cholesterol and lipid biosynthesis. Arch Toxicol 90, 3045–3060 (2016). https://doi.org/10.1007/s00204-016-1665-3

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  • DOI: https://doi.org/10.1007/s00204-016-1665-3

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