Imperial College London
Alternate

ProfessorIanWilson

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Visiting Professor
 
 
 
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Contact

 

i.wilson

 
 
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Location

 

311Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ekdahl:2018:10.1007/s00204-018-2274-0,
author = {Ekdahl, A and Weidolf, L and Baginski, M and Morikawa, Y and Thompson, RA and Wilson, ID},
doi = {10.1007/s00204-018-2274-0},
journal = {Archives of Toxicology},
pages = {2819--2828},
title = {The metabolic fate of fenclozic acid in chimeric mice with a humanized liver},
url = {http://dx.doi.org/10.1007/s00204-018-2274-0},
volume = {92},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The metabolic fate of the human hepatotoxin fenclozic acid ([2-(4-chlorophenyl)-1,3-thiazol-4-yl]acetic acid) (Myalex) was studied in normal and bile-cannulated chimeric mice with a humanized liver, following oral administration of 10 mg/kg. This in vivo animal model was investigated to assess its utility to study “human” metabolism of fenclozic acid, and in particular to explore the formation of electrophilic reactive metabolites (RMs), potentially unique to humans. Metabolism was extensive, particularly involving the carboxylic acid-containing side chain. Metabolism resulted in the formation of a large number of metabolites and involved biotransformation via both oxidative and conjugative routes. The oxidative metabolites detected included a variety of hydroxylations as well as cysteinyl-, N-acetylcysteinyl-, and cysteinylglycine metabolites. The latter resulted from the formation of glutathione adducts/conjugates providing evidence for the production of RMs. The production of other classes of RMs included acyl-glucuronides, and the biosynthesis of acyl carnitine, taurine, glutamine, and glycine conjugates via potentially reactive acyl-CoA intermediates was also demonstrated. A number of unique “human” metabolites, e.g., those providing evidence for side-chain extension, were detected in the plasma and excreta of the chimeric liver-humanized mice that were not previously characterised in, e.g., the excreta of rat and C57BL/6 mice. The different pattern of metabolism seen in these chimeric mice with a humanized liver compared to the conventional rodents may offer clues to the factors that contributed to the drug-induced liver injury seen in humans.
AU  - Ekdahl,A
AU  - Weidolf,L
AU  - Baginski,M
AU  - Morikawa,Y
AU  - Thompson,RA
AU  - Wilson,ID
DO  - 10.1007/s00204-018-2274-0
EP  - 2828
PY  - 2018///
SN  - 0340-5761
SP  - 2819
TI  - The metabolic fate of fenclozic acid in chimeric mice with a humanized liver
T2  - Archives of Toxicology
UR  - http://dx.doi.org/10.1007/s00204-018-2274-0
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000443424300006&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/65433
VL  - 92
ER  -
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