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Abstract :
[en] Background: Aristolochic acids (AA) are powerful nephrotoxic and carcinogenetic products derived from Aristolochiaceae responsible for acute to chronic renal failure and urothelial cancer complications in countries using traditional herbal medicine. Early detection of renal tubular injury could be useful in individuals at risk of exposure to AA. Methods: The Consortium of Metabonomic in Toxicicology (COMET) has developed predictive models of renal toxicity based on the NMR-based metabonomic evaluation of urine and serum samples collected from rats acutely exposed to various well characterized nephrotoxicants. Using this COMET protocol, we studied the metabonomic urine profile of rats exposed to one sc injection of AA I or II at different dosages (75, 100mg/kg). We then compared it to those obtained with 3 molecules known for their toxicity on the proximal tubule, i.e ifosfamide (Ifo: 7, 70mg/kg), gentamicin (Genta: 40, 400mg/kg) and cisplatin (Cis: 0.5, 5mg/kg), respectively.Results: Metabonomic results obtained in AA rats demonstrated a urinary increase in metabolites involved in osmoregulation (taurine, betaine, glycine), cell death (lactate) and in reabsorptive capacity of the tubular epithelium (glucose), and a significant reduction of Krebs's cycle components (alpha-ketoglutarate, succinate, citrate), suggesting a mitochondrial injury. The comparison of these AA profiles with those obtained with Ifo, Genta and Cis revealed close similarities in 2D plots. However, the 3D modelization approach showed very close score plots shared by AA, Ifo and Cis and a different behaviour exhibited by Genta samples. Conclusions: This metabonomic study confirms the mode of action of AA towards the proximal tubule and provides an original signature of induced mitochondrial insult. This approach could bring new insight in understanding the toxicity pathways of AA within the kidney. Moreover, it could be a useful tool of noninvasive screening in populations at risk of AA intoxication.
