Archives of Toxicology

, Volume 90, Issue 12, pp 3045–3060 | Cite as

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

  • Marcelo Dutra Arbo
  • Simone Melega
  • Regina Stöber
  • Markus Schug
  • Eugen Rempel
  • Jörg Rahnenführer
  • Patricio Godoy
  • Raymond Reif
  • Cristina Cadenas
  • Maria de Lourdes Bastos
  • Helena Carmo
  • Jan G. Hengstler
In vitro systems

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.

Keywords

Piperazine designer drugs Gene arrays Hepatotoxity Cholesterol metabolism 

Supplementary material

204_2016_1665_MOESM1_ESM.xlsx (72 kb)
Supplementary material 1 (XLSX 71 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Marcelo Dutra Arbo
    • 1
  • Simone Melega
    • 2
  • Regina Stöber
    • 2
  • Markus Schug
    • 2
  • Eugen Rempel
    • 3
  • Jörg Rahnenführer
    • 3
  • Patricio Godoy
    • 2
  • Raymond Reif
    • 2
  • Cristina Cadenas
    • 2
  • Maria de Lourdes Bastos
    • 1
  • Helena Carmo
    • 1
  • Jan G. Hengstler
    • 2
  1. 1.UCIBIO/REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de FarmáciaUniversidade do PortoPortoPortugal
  2. 2.Leibniz Research Centre for Working Environment and Human Factors (IFADO), Technical University of DortmundDortmundGermany
  3. 3.Department of StatisticsTechnical University of DortmundDortmundGermany

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