A metabonomic study on the biochemical effects of doxorubicin in rats using (1)H-NMR spectroscopy.
Metabonomic investigation of doxorubicin (adriamycin) was carried out in male Sprague-Dawley rats using high-resolution (1)H 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.
Park
Jong-Chul
JC
Korea Basic Science Institute, Seoul, South Korea.
Hong
Young-Shick
YS
Kim
Yeon Joo
YJ
Yang
Ji-Young
JY
Kim
Eun-Young
EY
Kwack
Seung Jun
SJ
Ryu
Do Hyun
DH
Hwang
Geum-Sook
GS
Lee
Byung Mu
BM
D000818:Animals; D015415:Biomarkers; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D016018:Least-Squares Analysis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics; D008744:Methylamines / Q000378:metabolism / Q000652:urine; D015999:Multivariate Analysis; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D015415:Biomarkers; D008744:Methylamines; D004317:Doxorubicin; C005855:trimethyloxamine