[Metabonomics profile of urine from rats administrated with different treatment period of isoniazid].
OBJECTIVE
To study the effect of different treatment period, of isoniazid (INH) on the metabonomic profile of rat urine and its relationship with traditional toxicity evaluation of blood biochemical indicators and histopathology and to explore the feasibility of metabonomics in the application of drug toxicity.


METHODS
Sixty male Wistar rats were orally administrated with 0, 50, 100, 200, and 400 mg x kg(-1) INH for 3, 7, and 14 days, respectively. Rat urine was then collected and its 1H nuclear magnetic resonance (NMR) spectra were acquired. All animals underwent traditional toxicity evaluation.


RESULTS
Hepatotoxicity was revealed by traditional toxicity evaluation in rats treated with higher dosage and longer treatment of INH. Time-response relationship existed during the treatment. Time-dependent metabonomics changes conformed with the results of traditional toxicity evaluation. The urine metabonomics showed a trajectory bias from those of the controls or pre-administration, and such bias exaggerated along with the prolongation of treatment, indicating a severer toxic injury. Along with the increase of the concentrations of urinary taurine and glucose and the decrease of the concentrations of urinary citrate and 2-oxoglutarate, the 1H NMR spectra of urine in rats treated with INH also changed.


CONCLUSIONS
The metabonomics technique can distinguish the onset and development of toxicity, which helps track and identify biomarkers. The hepatic toxicity induced by INH is related to the injury of mitochondrial function, reduction of energy metabolism in tricarboxylic acid cycle, and perturbations in the metabolism of glucose and lipid. The effect of INH on the rat urine metabonomic profile is related with INH toxicology. Therefore, metabonomics can be recognized as an ideal technique to explore and evaluate the drug toxicities.
Liao
Yan
Y
Research and Evaluation Center for Toxicology, Beijing Institute of Disease Control and Prevention, Beijing 100071, China.
Peng
Shuang-Qing
SQ
Yan
Xian-Zhong
XZ
Zhang
Li-Shi
LS
D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity*; D015415:Biomarkers / Q000737:chemistry / Q000652:urine*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000652:urine; D019343:Citric Acid / Q000737:chemistry / Q000652:urine; D002952:Citric Acid Cycle / Q000187:drug effects; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D007538:Isoniazid / Q000633:toxicity*; D007656:Ketoglutaric Acids / Q000737:chemistry / Q000652:urine; D008055:Lipids; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000737:chemistry / Q000652:urine; D018675:Toxicity Tests / Q000379:methods
D000995:Antitubercular Agents; D015415:Biomarkers; D007656:Ketoglutaric Acids; D008055:Lipids; D013654:Taurine; D019343:Citric Acid; D005947:Glucose; D007538:Isoniazid