Metabonomic Study Of Toxicity Of Fu Zi And Its Main Toxic Components On Rats

Fu Zi (Radix Aconiti Lateralis Preparata), a widely used traditional Chinese herbal medicine with a variety of functions, has strong cardiac and central nerve system toxicity due to its contents of diester alkaloids. In this paper, the effects of Fu Zi and its three main diester alkaloids on the changes of metabolic profiles of rats were studied by using NMR-based metabonomic techniques, their toxicological characteristics were described. The potential applications of metabonomics in the safety evaluation of traditional Chinese medicine were also discussed.Male Wistar rats were administered orally with the decoctions of sliced black Fu Zi or unprocessed Fu Zi in high,middle and low dosages or distilled water for 14 days. Urine samples collected at different time points and the plasma and tissue samples collected at the last day of experiment were analyzed by 1H NMR spectroscopy. Spectral characteristics for each group were summarized and the data were analyzed by principal component analysis (PCA). Urinary taurine level in the groups dosed with sliced black Fu Zi decoction decreased in the early stage of drug administration as compared with that of the controls, and then recovered to the normal level at the later stage, in a dose dependent manner. However, different process was also observed for the groups dosed with the decoction of unprocessed Fu Zi with the increased taurine in the rat urine, which may reflect the effect of processing on the toxicity. The levels of acetate, citrate and succinate were also altered.The acute and subacute effects on the metabolic profiles of rats, of the three main toxic components of Fu Zi, aconitine, mesaconitine and hypaconitine, were also studied. The results of acute toxicity experiment indicated that maximum changes of urinary metabolite levels were observed at 6h~12h post dose. The taurine level in dosed groups then decreased and the acetate level kept increasing, which may be an indication of renal toxicity. The results of subacute toxicity experiments indicated the decreased taurine level in urine and heart tissue, increased lactate level in plasma and increased levels of glutamate, choline,β-hydroxybutyrate in the aqueous extracts of brain tissues of dosed groups as compared with controls. The results of present studies suggest that metabonomic techniques can be used to characterize the metabolic consequence Fu Zi and its toxic alkaloids component, to elucidate the toxic their effects and mechanism. These results also suggest that metabonomics is a promising new technology for the safety evaluation of traditional Chinese medicine.