Metabonomics study of the effects of pretreatment with glycyrrhetinic acid on mesaconitine-induced toxicity in rats.
BACKGROUND
Aconitum carmichaelii Debx. (Fuzi), a commonly use traditional Chinese medicine (TCM), has often been used in combination with Rhizoma Glycyrrhizae (Gancao) to reduce its toxicity due to diester diterpenoid alkaloids aconitine, mesaconitine, and hypaconitine. However, the mechanism of detoxication is still unclear. Glycyrrhetinic acid (GA) is the metabolite of glycyrrhizinic acid (GL), the major component of Gancao. In present study, the effect of GA on the changes of metabolic profiles induced by mesaconitine was investigated using NMR-based metabolomic approaches.


METHODS
Fifteen male Wistar rats were divided into a control group, a group administered mesaconitine alone, and a group administered mesaconitine with one pretreatment with GA. Their urine samples were used for NMR spectroscopic metabolic profiling. Statistical analyses such as orthogonal projections to latent structures-discriminant analysis (OPLS-DA), t-test, hierarchical cluster, and pathway analysis were used to detect the effects of pretreatment with GA on mesaconitine-induced toxicity.


RESULTS
The OPLS-DA score plots showed the metabolic profiles of GA-pretreated rats apparently approach to those of normal rats compared to mesaconitine-induced rats. From the t-test and boxplot results, the concentrations of leucine/isoleucine, lactate, acetate, succinate, trimethylamine (TMA), dimethylglycine (DMG), 2-oxo-glutarate, creatinine/creatine, glycine, hippurate, tyrosine and benzoate were significantly changed in metabolic profiles of mesaconitine-induced rats. The disturbed metabolic pathways include amino acid biosynthesis and metabolism.


CONCLUSIONS
GA-pretreatment can mitigate the metabolic changes caused by mesaconitine-treatment on rats, indicating that prophylaxis with GA could reduce the toxicity of mesaconitine at the metabolic level.
National Center of Biomedical Analysis, 27 Taiping Road, Beijing 100850, PR China.
Bo
B
Sun
National Center of Biomedical Analysis, 27 Taiping Road, Beijing 100850, PR China; Department of Analytical Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Ming
M
Zhang
National Center of Biomedical Analysis, 27 Taiping Road, Beijing 100850, PR China.
Qi
Q
Zhang
National Center of Biomedical Analysis, 27 Taiping Road, Beijing 100850, PR China.
Kunpeng
K
Ma
National Center of Biomedical Analysis, 27 Taiping Road, Beijing 100850, PR China.
Haijing
H
Li
Department of Analytical Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Famei
F
Li
National Center of Biomedical Analysis, 27 Taiping Road, Beijing 100850, PR China.
Fangting
F
Dong
National Center of Biomedical Analysis, 27 Taiping Road, Beijing 100850, PR China. Electronic address: yanxz@proteomics.cn.
Xianzhong
X
Yan
D000157:Aconitine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D000596:Amino Acids / Q000096:biosynthesis / Q000378:metabolism / Q000652:urine; D000818:Animals; D016002:Discriminant Analysis; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D006331:Heart Diseases / Q000139:chemically induced / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics; D011522:Protons; D051381:Rats; D017208:Rats, Wistar; D012768:Shivering / Q000187:drug effects; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy
D000596:Amino Acids; D011522:Protons; C019470:mesaconitine; D006034:Glycyrrhetinic Acid; D000157:Aconitine
Glycyrrhetinic acid; Mesaconitine; Metabolomics; NMR