PMID- 27255387
OWN - NLM
STAT- MEDLINE
DCOM- 20180402
LR  - 20180420
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 153
IP  - 1
DP  - 2016 Sep
TI  - Editor's Highlight: Characterization of Hepatotoxicity Mechanisms Triggered by 
      Designer Cathinone Drugs (beta-Keto Amphetamines).
PG  - 89-102
LID - 10.1093/toxsci/kfw105 [doi]
AB  - The use of cathinone designer drugs in recreational settings has been associated 
      with severe toxic effects, including liver damage. The precise mechanisms by 
      which cathinones induce hepatotoxicity and whether they act by common pathways 
      remain to be elucidated. Herein, we assessed the toxicity of the cathinones 
      methylone, pentedrone, 3,4-methylenedioxypyrovalerone (MDPV) and 
      4-methylethcathinone (4-MEC) in primary rat hepatocytes (PRH) and HepaRG cells, 
      and compared with that of 3,4-methylenedioxymethamphetamine (MDMA). MDPV and 
      pentedrone were significantly more toxic than MDMA, while methylone was the least 
      cytotoxic compound. Importantly, PRH revealed to be the most sensitive 
      experimental model and was thus used to explore the mechanisms underlying the 
      observed toxicity. All drugs elicited the formation of reactive oxygen and 
      nitrogen species (ROS and RNS), but more markedly for methylone, pentedrone and 
      4-MEC. GSH depletion was also a common effect at the highest concentration 
      tested, whereas only MDPV and pentedrone caused a significant decrease in ATP 
      levels. The antioxidants ascorbic acid or N-acetyl-L-cysteine partially 
      attenuated the observed cell death. All cathinones triggered significant caspase 
      activation and apoptosis, which was partially reversed by the caspase inhibitor 
      Ac-LETD-CHO. In conclusion, the present data shows that (1) cathinones induce in 
      vitro hepatotoxic effects that vary in magnitude among the different analogues, 
      (2) oxidative stress and mitochondrial dysfunction play a role in 
      cathinones-induced hepatic injury, and (3) apoptosis appears to be an important 
      pathway of cell death elicited by these novel drugs.
CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the Society 
      of Toxicology. All rights reserved. For Permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Valente, Maria Joao
AU  - Valente MJ
AD  - *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Porto, Portugal; mcarv@ufp.edu.pt.
FAU - Araujo, Ana Margarida
AU  - Araujo AM
AD  - *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Porto, Portugal;
FAU - Bastos, Maria de Lourdes
AU  - Bastos Mde L
AD  - *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Porto, Portugal;
FAU - Fernandes, Eduarda
AU  - Fernandes E
AD  - UCIBIO, REQUIMTE, Laboratory of Applied Chemistry, Faculty of Pharmacy, 
      University of Porto, Porto, Portugal;
FAU - Carvalho, Felix
AU  - Carvalho F
AD  - *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Porto, Portugal;
FAU - Guedes de Pinho, Paula
AU  - Guedes de Pinho P
AD  - *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Porto, Portugal;
FAU - Carvalho, Marcia
AU  - Carvalho M
AD  - *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Porto, Portugal; FP-ENAS, CEBIMED, Fundacao Ensino e Cultura Fernando 
      Pessoa, Porto, Portugal mcarv@ufp.edu.pt.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160602
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Alkaloids)
RN  - 0 (Antioxidants)
RN  - 0 (Designer Drugs)
RN  - 540EI4406J (cathinone)
SB  - IM
MH  - Alkaloids/*toxicity
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Apoptosis/drug effects
MH  - Cells, Cultured
MH  - Designer Drugs/*toxicity
MH  - Liver/*drug effects
MH  - Male
MH  - Models, Biological
MH  - Oxidative Stress/drug effects
MH  - Rats
MH  - Rats, Wistar
OTO - NOTNLM
OT  - apoptosis
OT  - hepatotoxicity
OT  - oxidative stress
OT  - synthetic cathinones
OT  - beta-keto amphetamines
EDAT- 2016/06/04 06:00
MHDA- 2018/04/03 06:00
CRDT- 2016/06/04 06:00
PHST- 2016/06/04 06:00 [entrez]
PHST- 2016/06/04 06:00 [pubmed]
PHST- 2018/04/03 06:00 [medline]
AID - kfw105 [pii]
AID - 10.1093/toxsci/kfw105 [doi]
PST - ppublish
SO  - Toxicol Sci. 2016 Sep;153(1):89-102. doi: 10.1093/toxsci/kfw105. Epub 2016 Jun 2.