PMID- 33550444
OWN - NLM
STAT- MEDLINE
DCOM- 20211103
LR  - 20211103
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Linking)
VI  - 95
IP  - 4
DP  - 2021 Apr
TI  - From street to lab: in vitro hepatotoxicity of buphedrone, butylone and 3,4-DMMC.
PG  - 1443-1462
LID - 10.1007/s00204-021-02990-9 [doi]
AB  - 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, alpha-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 EC(50) 
      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.
FAU - Roque Bravo, Rita
AU  - Roque Bravo R
AUID- ORCID: 0000-0002-2257-6903
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313, Porto, Portugal. 
      rita.rdsb@gmail.com.
FAU - Carmo, Helena
AU  - Carmo H
AUID- ORCID: 0000-0002-6650-5285
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313, Porto, Portugal.
FAU - Valente, Maria Joao
AU  - Valente MJ
AUID- ORCID: 0000-0001-6162-2426
AD  - UCIBIO, REQUIMTE, Laboratory of Biochemistry, Faculty of Pharmacy, University of 
      Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313, Porto, Portugal.
FAU - Silva, Joao Pedro
AU  - Silva JP
AUID- ORCID: 0000-0002-5656-0897
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313, Porto, Portugal.
FAU - Carvalho, Felix
AU  - Carvalho F
AUID- ORCID: 0000-0003-3858-3494
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313, Porto, Portugal.
FAU - Bastos, Maria de Lourdes
AU  - Bastos ML
AUID- ORCID: 0000-0001-9895-503X
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313, Porto, Portugal.
FAU - Dias da Silva, Diana
AU  - Dias da Silva D
AUID- ORCID: 0000-0002-7331-9157
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua de Jorge Viterbo Ferreira No. 228, 4050-313, Porto, Portugal. 
      up538058@g.uporto.pt.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210207
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (Butyrophenones)
RN  - 0 (Designer Drugs)
RN  - 0 (Methylamines)
RN  - 0 (Propiophenones)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - C4EW58DTW5 (3,4-dimethylmethcathinone)
RN  - VD73947M0O (buphedrone)
RN  - X72T4EQ4FQ (2-methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/administration & dosage/*analogs & 
      derivatives/toxicity
MH  - Animals
MH  - Autophagy/drug effects
MH  - Butyrophenones/administration & dosage/*toxicity
MH  - Cell Line, Tumor
MH  - Chemical and Drug Induced Liver Injury/*etiology/pathology
MH  - Designer Drugs/administration & dosage/toxicity
MH  - Dose-Response Relationship, Drug
MH  - Hep G2 Cells
MH  - Hepatocytes/drug effects/pathology
MH  - Humans
MH  - Male
MH  - Methylamines/administration & dosage/*toxicity
MH  - Oxidative Stress/drug effects
MH  - Propiophenones/administration & dosage/*toxicity
MH  - Rats
MH  - Rats, Wistar
OTO - NOTNLM
OT  - Apoptosis
OT  - Autophagy
OT  - CYP2D6
OT  - CYP2E1
OT  - CYP3A4
OT  - Liver toxicity
OT  - Necrosis
OT  - New psychoactive substances (NPS)
EDAT- 2021/02/08 06:00
MHDA- 2021/11/04 06:00
CRDT- 2021/02/07 20:52
PHST- 2020/11/18 00:00 [received]
PHST- 2021/01/21 00:00 [accepted]
PHST- 2021/02/08 06:00 [pubmed]
PHST- 2021/11/04 06:00 [medline]
PHST- 2021/02/07 20:52 [entrez]
AID - 10.1007/s00204-021-02990-9 [pii]
AID - 10.1007/s00204-021-02990-9 [doi]
PST - ppublish
SO  - Arch Toxicol. 2021 Apr;95(4):1443-1462. doi: 10.1007/s00204-021-02990-9. Epub 
      2021 Feb 7.