Advertisement

Neurotoxicity Research

, Volume 30, Issue 2, pp 239–250 | Cite as

Cytotoxic Activity of Pyrovalerone Derivatives, an Emerging Group of Psychostimulant Designer Cathinones

  • Jakub Wojcieszak
  • Dariusz Andrzejczak
  • Agata Woldan-Tambor
  • Jolanta B. Zawilska
Original Article

Abstract

The growing popularity of novel psychoactive substances (NPS) has aroused the concerns of public health specialists. The pyrovalerone derivatives are a branch of synthetic cathinones, a very popular group of psychostimulant NPS. Despite numerous case reports of fatal intoxications, little is known about the cytotoxicity of these substances. Therefore, this study was aimed to evaluate the toxic properties of pyrovalerone, its highly prevalent derivative 3,4-methylenedioxypyrovalerone (3,4-MDPV) with its two major metabolites (catechol-MDPV and methylcatechol-MDPV) and the structural isomer 2,3-MDPV, together with newer members of the group, i.e., α-pyrrolidinovalerothiophenone (α-PVT) and α-pyrrolidinooctanophenone (PV9), using model human cell lines for neurons (SH-SY5Y), hepatocytes (Hep G2), and upper airway epithelium (RPMI 2650). We found that the first generation pyrovalerones (pyrovalerone, 3,4-MDPV, and 2,3-MDPV) produced a modest decrease of mitochondrial activity in the three examined cell lines, but were active in lower concentrations than methamphetamine used as a reference psychostimulant compound. Since catechol-MDPV displayed greater toxic potential than the parent compound, we suggest that the toxicity of 3,4-MDPV could be attributed to activity of this metabolite. Strikingly, the two new generation pyrovalerones, α-PVT and PV9, seem to be the most potent cytotoxic compounds: both induced highly pronounced mitochondrial dysfunction; the latter also demonstrated significant damage to cell membranes. The reported in vitro toxic activity of pyrovalerone cathinones against different cell types reinforces existing concerns regarding the health risks associated with the intake of these drugs.

Keywords

Novel psychoactive substances Synthetic cathinones Pyrovalerones MDPV PV9 Toxicity SH-SY5Y Hep G2 RPMI 2650 

Notes

Acknowledgments

Supported by the National Science Centre (NCN), Cracow, Poland (Grant No. 2014/13/B/NZ7/02237).

References

  1. Araújo AM, Valente MJ, Carvalho M, Dias da Silva D, Gaspar H, Carvalho F, de Lourdes Bastos M, Guedes de Pinho P (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. doi: 10.1007/s00204-014-1278-7 CrossRefPubMedGoogle Scholar
  2. Borek HA, Holstege CP (2012) Hyperthermia and multiorgan failure after abuse of “bath salts” containing 3,4-methylenedioxypyrovalerone. Ann Emerg Med 60(1):103–105. doi: 10.1016/j.annemergmed.2012.01.005 CrossRefPubMedGoogle Scholar
  3. den Hollander B, Sundström M, Pelander A, Ojanperä I, Mervaala E, Korpi ER, Kankuri E (2014) Keto amphetamine toxicity-focus on the redox reactivity of the cathinone designer drug mephedrone. Toxicol Sci 141(1):120–131. doi: 10.1093/toxsci/kfu108 CrossRefGoogle Scholar
  4. den Hollander B, Sundström M, Pelander A, Siltanen A, Ojanperä I, Mervaala E, Korpi ER, Kankuri E (2015) Mitochondrial respiratory dysfunction due to the conversion of substituted cathinones to methylbenzamides in SH-SY5Y cells. Sci Rep 5:14924. doi: 10.1038/srep14924 CrossRefGoogle Scholar
  5. Elliott SP (2005) MDMA and MDA concentrations in antemortem and postmortem specimens in fatalities following hospital admission. J Anal 29(5):296–300Google Scholar
  6. EMCDDA (2014) Report on the risk assessment of 1-(1,3-benzodioxol-5-yl)-2-(pyrrolidin-1-yl) pentan-1-one (3,4-methylenedioxypyrovalerone, MDPV) in the framework of the Council Decision on new psychoactive substances. http://www.emcdda.europa.eu/attachements.cfm/att_228256_EN_TDAK14003ENN.pdf. Retrieved 22 Oct 2014
  7. EMCDDA (2015a) New psychoactive substances in Europe. An update from the EU Early Warning System (March 2015). http://www.emcdda.europa.eu/attachements.cfm/att_235958_EN_TD0415135ENN.pdf. Accessed 23 April 2015
  8. EMCDDA (2015b) α-PVP EMCDDA-Europol joint report on a new psychoactive substance: 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP). http://www.emcdda.europa.eu/attachements.cfm/att_242501_EN_TDAS15001ENN.pdf. Accessed 30 Sept 2015
  9. Fröhlich S, Lambe E, O’Dea J (2011) Acute liver failure following recreational use of psychotropic “head shop” compounds. Ir J Med Sci 180(1):263–264. doi: 10.1007/s11845-010-0636-6 CrossRefPubMedGoogle Scholar
  10. Glennon RA (2014) Bath salts, mephedrone, and methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention. Adv Pharmacol 69:581–620. doi: 10.1016/B978-0-12-420118-7.00015-9 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Gregg RA, Rawls SM (2014) Behavioral pharmacology of designer cathinones: a review of the preclinical literature. Life Sci 97(1):27–30. doi: 10.1016/j.lfs.2013.10.033 CrossRefPubMedGoogle Scholar
  12. Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, Suzuki O, Watanabe K (2014) Identification and quantitation of a new cathinone designer drug PV9 in an “aroma liquid” product, antemortem whole blood and urine specimens, and a postmortem whole blood specimen in a fatal poisoning case. Forensic Toxicol 32(2):243–250. doi: 10.1007/s11419-014-0230-0 CrossRefGoogle Scholar
  13. Kikura-Hanajiri R, Kawamura NU, Goda Y (2014) Changes in the prevalence of new psychoactive substances before and after the introduction of the generic scheduling of synthetic cannabinoids in Japan. Drug Test Anal 6(7–8):832–839. doi: 10.1002/dta.1584 CrossRefPubMedGoogle Scholar
  14. Knasmüller S, Mersch-Sundermann V, Kevekordes S, Darroudi F, Huber WW, Hoelzl C, Bichler J, Majer BJ (2004) Use of human-derived liver cell lines for the detection of environmental and dietary genotoxicants; current state of knowledge. Toxicology 198(1–3):315–328. doi: 10.1016/j.tox.2004.02.008 CrossRefPubMedGoogle Scholar
  15. Kudo K, Usumoto Y, Kikura-Hanajiri R, Sameshima N, Tsuji A, Ikeda N (2015) A fatal case of poisoning related to new cathinone designer drugs, 4-methoxy PV8, PV9, and 4-methoxy PV9, and a dissociative agent, diphenidine. Legal Med (Tokyo) 17(5):421–426. doi: 10.1016/j.legalmed.2015.06.005 CrossRefGoogle Scholar
  16. Liechti M (2015) Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signaling. Swiss Med Wkly 145:w14043. doi: 10.4414/smw.2015.14043 PubMedGoogle Scholar
  17. Maciów-Głąb M, Rojek S, Kula K, Kłys M (2014) “New designer drugs” in aspects of forensic toxicology. Arch Med Sadowej Kryminol 64(1):20–33. doi: 10.5114/amsik.2014.44587 PubMedGoogle Scholar
  18. Marinetti LJ, Antonides HM (2013) Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results. J Anal Toxicol 37(3):135–146. doi: 10.1093/jat/bks136 CrossRefPubMedGoogle Scholar
  19. Meyer MR, Du P, Schuster F, Maurer HH (2010) Studies on the metabolism of the α-pyrrolidinophenone designer drug methylenedioxypyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS. J Mass Spectrom 45(12):1426–1442. doi: 10.1002/jms.1859 CrossRefPubMedGoogle Scholar
  20. Nagai H, Saka K, Nakajima M, Maeda H, Kuroda R, Igarashi A, Tsujimura-Ito T, Nara A, Komori M, Yoshida K (2014) Sudden death after sustained restraint following self-administration of the designer drug α-pyrrolidinovalerophenone. Int J Cardiol 172:263–265. doi: 10.1016/j.ijcard.2013.12.262 CrossRefPubMedGoogle Scholar
  21. Nakagawa Y, Suzuki T, Tayama S, Ishii H, Ogata A (2009) Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its analogues, on isolated rat hepatocytes. Arch Toxicol 83(1):69–80. doi: 10.1007/s00204-008-0323-9 CrossRefPubMedGoogle Scholar
  22. Paillet-Loilier M, Cesbron A, Le Boisselier R, Bourgine J, Debruyne D (2014) Emerging drugs of abuse: current perspectives on substituted cathinones. Subst Abuse Rehabil 5:37–52. doi: 10.2147/SAR.S37257 PubMedPubMedCentralGoogle Scholar
  23. Penders TM, Gestring RE, Vilensky DA (2012). Intoxication delirium following use of synthetic cathinone derivatives. Am J Drug Alcohol Abuse 38(6):616–617. doi: 10.3109/00952990 CrossRefPubMedGoogle Scholar
  24. Reichl S, Becker K (2012) Cultivation of RPMI 2650 cells as an in vitro model for human transmucosal nasal drug absorption studies: optimization of selected culture conditions. J Pharm Pharmacol 64(11):1621–1630. doi: 10.1111/j.2042-7158.2012.01540.x CrossRefPubMedGoogle Scholar
  25. Rickli A, Hoener MC, Liechti ME (2015) Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones. Eur Neuropsychopharmacol 25(3):365–376. doi: 10.1016/j.euroneuro.2014.12.012 CrossRefPubMedGoogle Scholar
  26. Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME (2013) Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 168(2):458–470. doi: 10.1111/j.1476-5381.2012.02145.x CrossRefPubMedGoogle Scholar
  27. Stevenson R, Tuddenham L (2014) Novel psychoactive substance intoxication resulting in attempted murder. J Forensic Leg Med 25:60–61. doi: 10.1016/j.jflm.2014.04.007 CrossRefPubMedGoogle Scholar
  28. Strano-Rossi S, Cadwallader AB, de la Torre X, Botrè F (2010) Toxicological determination and in vitro metabolism of the designer drug methylenedioxypyrovalerone (MDPV) by gas chromatography/mass spectrometry and liquid chromatography/quadrupole time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 24(18):2706–2714. doi: 10.1002/rcm.4692 CrossRefPubMedGoogle Scholar
  29. Uchiyama N, Matsuda S, Kawamura M, Kikura-Hanajiri R, Goda Y (2013) Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products. Forensic Toxicol 31(2):223–240. doi: 10.1007/s11419-013-0182-9 CrossRefGoogle Scholar
  30. Uchiyama N, Matsuda S, Kawamura M, Shimokawa Y, Kikura-Hanajiri R, Aritake K, Urade Y, Goda Y (2014) Characterization of four new designer drugs, 5-chloro-NNEI, NNEI indazole analog, α-PHPP and α-POP, with 11 newly distributed designer drugs in illegal products. Forensic Sci Int 243:1–13. doi: 10.1016/j.forsciint.2014.03.013 CrossRefPubMedGoogle Scholar
  31. Valente MJ, Araújo AM, Silva R, Bastos ML, Carvalho F, Guedes de Pinho P, Carvalho M (2015) 3,4-Methylenedioxypyrovalerone (MDPV): in vitro mechanisms of hepatotoxicity under normothermic and hyperthermic conditions. Arch Toxicol. doi: 10.1007/s00204-015-1653-z Google Scholar
  32. Xie H, Hu L, Li G (2010) SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson’s disease. Chin Med J 123:1086–1092PubMedGoogle Scholar
  33. Zawilska JB (2015) “Legal highs”—an emerging epidemic of novel psychoactive substances. Int Rev Neurobiol 120:273–300. doi: 10.1016/bs.irn.2015.02.009 CrossRefPubMedGoogle Scholar
  34. Zawilska JB, Andrzejczak D (2015) Next generation of the novel psychoactive substances on the horizon—a complex problem to face. Drug Alcohol Depend 157:1–17. doi: 10.1016/j.drugalcdep.2015.09.030 CrossRefPubMedGoogle Scholar
  35. Zawilska JB, Wojcieszak J (2013) Designer cathinones—an emerging class of novel recreational drugs. Forensic Sci Int 231(1–3):42–53. doi: 10.1016/j.forsciint.2013.04.015 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jakub Wojcieszak
    • 1
  • Dariusz Andrzejczak
    • 1
  • Agata Woldan-Tambor
    • 1
  • Jolanta B. Zawilska
    • 1
  1. 1.Department of PharmacodynamicsMedical University of ŁódźLodzPoland

Personalised recommendations