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Abstract
Metabonomic investigation of doxorubicin (adriamycin) was carried out in male Sprague-Dawley rats using high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy coupled with multivariate statistics. Urine samples (d –1 to 7) from rats treated with doxorubicin at two dose levels (5 or 15 mg/kg body weight) were collected at each time point and doxorubicin-induced biomarkers were examined. Of metabolites, early elevated biochemical changes were observed in trimethylamine N-oxide (TMAO) levels suggesting renal dysfunction. Perturbation in TMAO was maximal in the low-dose group at 48 h post dose (p.d.) and returned to control at 168 h p.d., indicating recovery from renal toxicity induced by doxorubicin. After doxorubicin administration, the high-dose group was divided into low and high responders at 48 h and further divided into high, moderate, and no recovery animals at 96 h, indicating individual susceptible response to drug-induced toxicity. Urinary increases in glucose, lactate, alanine, and valine suggested progression of renal damage resulting in glycosuria, lactic aciduria, and aminoaciduria up to 168 h in the high-dose group. Urinary elevation of creatine and phenylacetylglycine (PAG) together with reduction of N-methylnicotinic acid (NMNA) and hippurate levels was suggestive of liver injury in the high-dose group. Impairment of energy metabolism was also indicated by decreased levels of tricarboxylic acid cycle intermediates in urine of rats treated with high-dose doxorubicin. This study highlights the applicability of NMR-based metabonomics with multivariate statistics for monitoring biomarkers produced by doxorubicin treatments.
This research was supported by a grant (07152KFDA627) from the Korea Food and Drug Administration in 2007 and a grant (2006-KRF-531-C00038) from the Korea Research Foundation. This work was also partially supported by a Korea University Grant.
Notes
Jong-Chul Park and Young-Shick Hong contributed equally to this article.