Imperial College London
Portrait Picture

DrWafaKhamri

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Senior Teaching Fellow
 
 
 
//

Contact

 

w.khamri

 
 
//

Location

 

Queen Elizabeth the Queen Mother Wing (QEQM)St Mary's Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Possamai:2014:10.1111/liv.12689,
author = {Possamai, LA and McPhail, MJW and Khamri, W and Wu, B and Concas, D and Harrison, M and Williams, R and Cox, RD and Cox, IJ and Anstee, QM and Thursz, MR},
doi = {10.1111/liv.12689},
journal = {Liver International},
pages = {764--773},
title = {The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity},
url = {http://dx.doi.org/10.1111/liv.12689},
volume = {35},
year = {2014}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background & AimsVariations in intestinal microbiota may influence acetaminophen metabolism. This study aimed to determine whether intestinal microbiota are a source of differential susceptibility to acetaminophen-induced hepatotoxicity.MethodsConventionally housed C3H/HeH (CH) and C3H/HeH germ-free (GF) mice were administered a 200 mg/kg IP dose of acetaminophen. The severity of hepatotoxicity at 8 h was assessed by histology and biochemical indices. A urinary metabolic profile was obtained using 1H-NMR. Baseline hepatic glutathione content and CYP2E1 expression were quantified. An additional group of C3H/HeJ (LPS-r) mice were assessed to determine the contribution of LPS/TLR4 signalling.ResultsBaseline glutathione levels were significantly reduced (P = 0.03) in GF mice. CYP2E1 mRNA expression and protein levels were not altered. Interindividual variability did not differ between GF and CH groups. No significant differences in the extent of hepatocellular injury (ALT or percentage necrosis) were demonstrated. However, a milder acute liver failure (ALF) phenotype was shown in GF compared with CH mice, with reduced plasma bilirubin and creatinine and increased blood glucose. Differential acetaminophen metabolism was demonstrated. GF mice displayed a higher urinary acetaminophen-sulphate:glucuronide ratio compared with CH (P = 0.01). Urinary analysis showed metabolic differentiation of GF and CH groups at baseline and 8 h (cross-validated anova P = 1 × 10-22). Interruption of TLR4 signalling in LPS-r mice had additional protective effects.ConclusionVariations in intestinal microbiota do not fully explain differential susceptibility to acetaminophen-induced hepatotoxicity. GF mice experienced some protection from secondary complications following acetaminophen overdose and this may be mediated through reduced TLR4/LPS signalling.
AU  - Possamai,LA
AU  - McPhail,MJW
AU  - Khamri,W
AU  - Wu,B
AU  - Concas,D
AU  - Harrison,M
AU  - Williams,R
AU  - Cox,RD
AU  - Cox,IJ
AU  - Anstee,QM
AU  - Thursz,MR
DO  - 10.1111/liv.12689
EP  - 773
PY  - 2014///
SN  - 1478-3231
SP  - 764
TI  - The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity
T2  - Liver International
UR  - http://dx.doi.org/10.1111/liv.12689
UR  - http://hdl.handle.net/10044/1/28091
VL  - 35
ER  -
Download