PMID- 22914986
OWN - NLM
STAT- MEDLINE
DCOM- 20130607
LR  - 20220408
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Linking)
VI  - 87
IP  - 1
DP  - 2013 Jan
TI  - AMAP, the alleged non-toxic isomer of acetaminophen, is toxic in rat and human 
      liver.
PG  - 155-65
LID - 10.1007/s00204-012-0924-1 [doi]
AB  - N-acetyl-meta-aminophenol (AMAP) is generally considered as a non-toxic 
      regioisomer of the well-known hepatotoxicant acetaminophen (APAP). However, so 
      far, AMAP has only been shown to be non-toxic in mice and hamsters. To 
      investigate whether AMAP could also be used as non-toxic analog of APAP in rat 
      and human, the toxicity of APAP and AMAP was tested ex vivo in precision-cut 
      liver slices (PCLS) of mouse, rat and human. Based on ATP content and 
      histomorphology, APAP was more toxic in mouse than in rat and human PCLS. 
      Surprisingly, although AMAP showed a much lower toxicity than APAP in mouse PCLS, 
      AMAP was equally toxic as or even more toxic than APAP at all concentrations 
      tested in both rat and human PCLS. The profile of proteins released into the 
      medium of AMAP-treated rat PCLS was similar to that of APAP, whereas in the 
      medium of mouse PCLS, it was similar to the control. Metabolite profiling 
      indicated that mouse PCLS produced the highest amount of glutathione conjugate of 
      APAP, while no glutathione conjugate of AMAP was detected in all three species. 
      Mouse also produced ten times more hydroquinone metabolites of AMAP, the assumed 
      proximate reactive metabolites, than rat or human. In conclusion, AMAP is toxic 
      in rat and human liver and cannot be used as non-toxic isomer of APAP. The marked 
      species differences in APAP and AMAP toxicity and metabolism underline the 
      importance of using human tissues for better prediction of toxicity in man.
FAU - Hadi, Mackenzie
AU  - Hadi M
AD  - Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, 
      University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The 
      Netherlands. m.hadi@rug.nl
FAU - Dragovic, Sanja
AU  - Dragovic S
FAU - van Swelm, Rachel
AU  - van Swelm R
FAU - Herpers, Bram
AU  - Herpers B
FAU - van de Water, Bob
AU  - van de Water B
FAU - Russel, Frans G M
AU  - Russel FG
FAU - Commandeur, Jan N M
AU  - Commandeur JN
FAU - Groothuis, Geny M M
AU  - Groothuis GM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120823
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 0 (Hydroquinones)
RN  - 0 (Proteins)
RN  - 362O9ITL9D (Acetaminophen)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - XV74C1N1AE (hydroquinone)
SB  - IM
MH  - Acetaminophen/metabolism/pharmacokinetics/*toxicity
MH  - Adenosine Triphosphate/metabolism
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Child
MH  - Female
MH  - Humans
MH  - Hydroquinones/metabolism
MH  - In Vitro Techniques
MH  - Isomerism
MH  - Liver/*drug effects/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Middle Aged
MH  - Proteins/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Species Specificity
MH  - Toxicity Tests/*methods
EDAT- 2012/08/24 06:00
MHDA- 2013/06/08 06:00
CRDT- 2012/08/24 06:00
PHST- 2012/07/30 00:00 [received]
PHST- 2012/08/06 00:00 [accepted]
PHST- 2012/08/24 06:00 [entrez]
PHST- 2012/08/24 06:00 [pubmed]
PHST- 2013/06/08 06:00 [medline]
AID - 10.1007/s00204-012-0924-1 [doi]
PST - ppublish
SO  - Arch Toxicol. 2013 Jan;87(1):155-65. doi: 10.1007/s00204-012-0924-1. Epub 2012 
      Aug 23.