An integrated metabonomic approach to describe temporal metabolic disregulation induced in the rat by the model hepatotoxin allyl formate.
The time-related metabolic events in rat liver, plasma, and urine following hepatotoxic insult with allyl formate (75 mg/kg) were studied using a combination of high-resolution liquid state and magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopic methods together with pattern recognition analysis. The metabonomics results were compared with the results of conventional plasma chemistry and histopathological assessments of liver damage. Various degrees of liver damage were observed in different animals, and this variation was reflected in all of the analyses. Furthermore, each analysis revealed a high degree of functional and structural recovery by the end of the study. The allyl formate-induced changes included hepatocellular necrosis, hepatic lipidosis, decreased liver glycogen and glucose, decreased plasma lipids, increased plasma creatine and tyrosine, increased urinary taurine and creatine, and decreased urinary TCA cycle intermediates. The observed reductions in hepatic glycogen and glucose suggest increased glucose utilization and are consistent with the expected depletion of hepatic ATP following mitochondrial impairment, assuming that there is a consequent increase in energy production from glycolysis. The increase in plasma tyrosine is consistent with impaired protein synthesis, a known consequence of ATP depletion. Partial least squares-based cross-correlation of the variation in the liver and plasma NMR profiles indicated that the allyl formate-induced increase in liver lipids correlated with the decrease in plasma lipids. This suggests disruption in lipid transport from the liver to plasma, which could arise through impaired apolipoprotein synthesis, as with ethionine.
Yap
Ivan K S
IK
Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics (SORA), Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London, SW7 2AZ United Kingdom.
Clayton
T Andrew
TA
Tang
Huiru
H
Everett
Jeremy R
JR
Hanton
Gilles
G
Provost
Jean-Pierre
JP
Le Net
Jean-Loic
JL
Charuel
Claude
C
Lindon
John C
JC
Nicholson
Jeremy K
JK
D000818:Animals; D001774:Blood Chemical Analysis; D056486:Chemical and Drug Induced Liver Injury; D003401:Creatine / Q000652:urine; D005563:Formic Acid Esters / Q000633:toxicity*; D005947:Glucose / Q000032:analysis; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D008112:Liver Glycogen / Q000032:analysis; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D013654:Taurine / Q000652:urine; D014443:Tyrosine / Q000097:blood
D005563:Formic Acid Esters; D008055:Lipids; D008112:Liver Glycogen; D013654:Taurine; D014443:Tyrosine; C034499:allyl formate; D005947:Glucose; D003401:Creatine