Carnitine, acylcarnitine and amino acid profiles analyzed by tandem mass spectrometry in a surfactant/virus mouse model of acute hepatic encephalopathy.
Tandem mass spectrometry (MS/MS) was used to analyze multiple serum metabolites for the first time in a surfactant/virus mouse model of acute hepatic encephalopathy (AHE). AHE is characterized by acute liver failure that can lead to potentially lethal increases in intracranial pressure. We have reproduced AHE in young CD-1 mice exposed from postnatal day (P) 2-13 to the industrial surfactant, Toximul 3409F (Tox), and then infected intranasally on P14 with sublethal doses (LD(10-30)) of mouse-adapted human influenza B (Lee) virus (FluB). The sera analyzed by MS/MS were from mice exhibiting typical markers of Tox-mediated potentiation of viral illness, including reduced weights and blood glucose levels. Most metabolite abnormalities were not evident until five days after viral infection (P19), the time corresponding to the onset of weight loss and mortality. Values for fatty acylcarnitines and amino acids in the Tox+FluB-treated mice were either additive or supra-additive relative to the effects of either treatment alone. Amino acid profiles were consistent with those reported for human AHE. None of the treated mice exhibited signs of carnitine deficiency, and propionylcarnitine levels were normal. On P19, mice given combined Tox+FluB treatment had significant increases in levels of both medium- and long-chain acylcarnitines (C6:0-C12:0 and C14:0-C20:0, respectively), including their monounsaturated metabolites. Levels of medium-chain dicarboxylic and long-chain hydroxy-acylcarnitines were also elevated in the combined treatment group. The results of this study indicate a diffuse mitochondrial dysfunction in Tox+FluB-treated mice that results in a serum metabolite profile unique from those observed in classic inherited metabolic disorders.
Murphy
M G
MG
Department of Physiology and Biophysics, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia, Canada. mary.murphy@dal.ca
Crocker
J F S
JF
O'Regan
P
P
Lee
S H S
SH
Geldenhuys
L
L
Dooley
K
K
Al-Khalidi
M
M
Acott
P D
PD
D000596:Amino Acids / Q000097:blood* / Q000737:chemistry; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood* / Q000737:chemistry; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000097:blood* / Q000139:chemically induced / Q000821:virology; D009981:Influenza B virus / Q000502:physiology*; D051379:Mice; D013501:Surface-Active Agents / Q000633:toxicity*; D053719:Tandem Mass Spectrometry; D013997:Time Factors
D000596:Amino Acids; D013501:Surface-Active Agents; C116917:acylcarnitine; D002331:Carnitine