Metabonomic investigations into hydrazine toxicity in the rat

The systemic biochemical effects of oral hydrazine administration (dosed at 75, 90, and 120 mg/kg) have been investigated in male Han Wistar rats usin g metabonomic analysis of H-1 NMR spectra of urine and plasma, conventional clinical chemistry, and liver histopathology. Plasma samples were collecte d both pre- and 24 h postdose, while urine was collected predose and daily over a 7 day postdose period. H-1 NMR spectra of the biofluids were analyze d visually and via pattern recognition using principal component analysis. The latter showed that there was a dose-dependent biochemical effect of hyd razine treatment on the levels of a range of low molecular weight compounds in urine and plasma, which was correlated with the severity of the hydrazi ne induced liver lesions. In plasma, increases in the levels of free glycin e, alanine, isoleucine, valine, lysine, arginine, tyrosine, citrulline, 3-D -hydroxybutyrate, creatine, histidine, and threonine were observed. Urinary excretion of hippurate, citrate, succinate, 2-oxoglutarate, trimethylamine -N-oxide, fumarate and creatinine were decreased following hydrazine dosing , whereas taurine, creatine, threonine, N-methylnicotinic acid, tyrosine, P -alanine, citrulline, N alpha -acetylcitrulline and argininosuccinate excre tion was increased. Moreover, the most notable effect was the appearance in urine and plasma of 2-aminoadipate, which has previously been shown to lea d to neurological effects in rats. High urinary levels of 2-aminoadipate ma y explain the hitherto poorly understood neurological effects of hydrazine. Metabonomic analysis of high-resolution H-1 NMR spectra of biofluids has p rovided a means of monitoring the progression of toxicity and recovery, whi le also allowing the identification of novel biomarkers of development and regression of the lesion.