Drug-Induced Impairment of Mitochondrial Fatty Acid Be- ta-Oxidation: A Metabonomic Evaluation in Rats

Drug-Induced Liver Diseases (DILI) is frequent and potentially
harmful. Steatosis, an accumulation of triglycerides in hepatocytes,
is a DILI that may be fatal in the long term. It progresses insidiously
and, due to the lack of obvious symptoms, is barely anticipated.
During lead optimization in drug development, it is crucial to screen
steatogenic molecules as early as possible. Unfortunately, to date,
the detection of steatosis in animals can only be histopathologically
ascertained. The present study aims to establish a non-invasive
urine metabolic signature of nascent steatosis in rats exposed to
some selected steatogenic model molecules. Metabonomics perfectly
meets this expectation and also provides a dynamic assessment
of the disease. In vivo, rat urine fractions can indeed be collected
over time in metabolic cages and analyzed by proton NMR
spectroscopy. This approach, combined with chemometric tools, can
give important mechanistic information on the biochemical pathways
which are possibly altered by the tested molecules. In the present
study, three prototypical compounds (valproic acid, tetracycline and
dimethylformamide) were evaluated by metabonomics in Wistar Han
rats to monitor the biochemical changes caused by the early development
of microvesicular steatosis in the first 24 hours following exposure.
A metabonomic pattern reflecting the consequences of the
inhibition of the beta-oxidation pathway emerged, mainly evidencing
trouble with energy production as well as in nitrogen metabolism.