Integrated metabonomic analysis of the multiorgan effects of hydrazine toxicity in the rat.
Hydrazine is a model toxin that induces both hepatotoxic and neurotoxic effects in experimental animals. The direct biochemical effects of hydrazine in kidney, liver, and brain tissue were assessed in male Sprague-Dawley rats using magic angle spinning nuclear magnetic resonance (NMR) spectroscopy. A single dose of hydrazine (90 mg/kg) resulted in changes to the biochemical composition of the liver after 24 h including an increase in triglycerides and beta-alanine, together with a decrease in hepatic glycogen, glucose, choline, taurine, and trimethylamine-N-oxide (TMAO). From histopathology measurements of liver tissue, minimal to mild hepatocyte alteration was observed in all animals at 24 h. The NMR spectra of the renal cortex at 24 h after dosing were dominated by a marked increase in the tissue concentration of 2-aminoadipate (2-AA) and beta-alanine, concomitant with depletions in TMAO, myo-inositol, choline, taurine, glutamate, and lysine. No alteration to the NMR spectral profile of the substantia nigra was observed after hydrazine administration, but perturbations to the relative concentrations of creatine, aspartate, myo-inositol, and N-acetyl aspartate were apparent in the hippocampus of hydrazine-treated animals at 24 h postdose. No overt signs of histopathological toxicity were observed in either the kidney or the brain regions examined. Elevated alanine levels were observed in all tissues indicative of a general inhibition of alanine transaminase activity. By 168 h postdose, NMR spectral profiles of treated rats appeared similar to those of matched controls for all tissue types indicative of recovery from toxic insult.
Garrod
Sarah
S
Imperial College of Science, Technology and Medicine, Exhibition Road, London SW7 2AZ, United Kingdom.
Bollard
Mary E
ME
Nicholls
Andrew W
AW
Connor
Susan C
SC
Connelly
John
J
Nicholson
Jeremy K
JK
Holmes
Elaine
E
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000037:antagonists & inhibitors; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006834:Hydrazines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D006834:Hydrazines; C029424:hydrazine; D000410:Alanine Transaminase