Bo Sun1, Xubin Wang2, Ruili Cao3, Qi Zhang4, Qiao Liu5, Meifeng Xu6, Ming Zhang7, Xiangbo Du8, Fangting Dong9, Xianzhong Yan10. 1. National Center of Biomedical Analysis, Beijing 100850, PR China. Electronic address: sunbo@proteomics.cn. 2. National Center of Biomedical Analysis, Beijing 100850, PR China. Electronic address: wangxubin2012@126.com. 3. National Center of Biomedical Analysis, Beijing 100850, PR China. Electronic address: crlmail@163.com. 4. National Center of Biomedical Analysis, Beijing 100850, PR China. Electronic address: ncba_nmr@126.com. 5. National Center of Biomedical Analysis, Beijing 100850, PR China; Chenzhou First People's Hospital, Chenzhou 423000, PR China. Electronic address: liuqiao.707@163.com. 6. National Center of Biomedical Analysis, Beijing 100850, PR China. Electronic address: xumeifeng103@126.com. 7. National Center of Biomedical Analysis, Beijing 100850, PR China; School of Pharmacy, Shengyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: zhangmingln@126.com. 8. National Center of Biomedical Analysis, Beijing 100850, PR China. Electronic address: d5194u@163.com. 9. National Center of Biomedical Analysis, Beijing 100850, PR China. Electronic address: dft@proteomics.cn. 10. National Center of Biomedical Analysis, Beijing 100850, PR China. Electronic address: yanxz@proteomics.cn.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi, the processed lateral root of Aconitum carmichaelii Debeaux, is a traditional Chinese medicine used for its analgesic, antipyretic, anti-rheumatoid arthritis and anti-inflammation effects; however, it is also well known for its toxicity. Gancao, the root of Glycyrrhiza uralensis Fisch., is often used concurrently with Fuzi to alleviate its toxicity. However, the mechanism of detoxication is still not well clear. AIM OF THE STUDY: In this study, the effect of Gancao on the metabolic changes induced by Fuzi was investigated by NMR-based metabonomic approaches. MATERIALS AND METHODS: Fifty male Wistar rats were randomly divided into five groups (group A: control, group B: Fuzi decoction alone, group C: Gancao decoction alone, group D: Fuzi decoction and Gancao decoction simultaneously, group E: Fuzi decoction 5h after Gancao decoction) and urine samples were collected for NMR-based metabolic profiling analysis. Statistical analyses such as unsupervised PCA, t-test, hierarchical cluster, and pathway analysis were used to detect the effects of Gancao on the metabolic changes induced by Fuzi. RESULTS: The behavioral and biochemical characteristics showed that Fuzi exhibited toxic effects on treated rats (group B) and statistical analyses showed that their metabolic profiles were in contrast to those in groups A and C. However, when Fuzi was administered with Gancao, the metabolic profiles became similar to controls, whereby Gancao reduced the levels of trimethylamine N-oxide, betaine, dimethylglycine, valine, acetoacetate, citrate, fumarate, 2-ketoglutarate and hippurate, and regulated the concentrations of taurine and 3-hydroxybutyrate, resulting in a decrease in toxicity. Furthermore, important pathways that are known to be involved in the effect of Gancao on Fuzi, including phenylalanine, tyrosine and tryptophan biosynthesis, the synthesis and degradation of ketone bodies, and the TCA cycle, were altered in co-treated rats. CONCLUSIONS: Gancao treatment mitigated the metabolic changes altered by Fuzi administration in rats, demonstrating that dosing with Gancao could reduce the toxicity of Fuzi at the metabolic level. Fuzi and Gancao administered simultaneously resulted in improved toxicity reduction than when Gancao was administrated 5h prior to Fuzi. In summary, co-administration of Gancao with Fuzi reduces toxicity at the metabolic level.
ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi, the processed lateral root of Aconitum carmichaelii Debeaux, is a traditional Chinese medicine used for its analgesic, antipyretic, anti-rheumatoid arthritis and anti-inflammation effects; however, it is also well known for its toxicity. Gancao, the root of Glycyrrhiza uralensis Fisch., is often used concurrently with Fuzi to alleviate its toxicity. However, the mechanism of detoxication is still not well clear. AIM OF THE STUDY: In this study, the effect of Gancao on the metabolic changes induced by Fuzi was investigated by NMR-based metabonomic approaches. MATERIALS AND METHODS: Fifty male Wistar rats were randomly divided into five groups (group A: control, group B: Fuzi decoction alone, group C: Gancao decoction alone, group D: Fuzi decoction and Gancao decoction simultaneously, group E: Fuzi decoction 5h after Gancao decoction) and urine samples were collected for NMR-based metabolic profiling analysis. Statistical analyses such as unsupervised PCA, t-test, hierarchical cluster, and pathway analysis were used to detect the effects of Gancao on the metabolic changes induced by Fuzi. RESULTS: The behavioral and biochemical characteristics showed that Fuzi exhibited toxic effects on treated rats (group B) and statistical analyses showed that their metabolic profiles were in contrast to those in groups A and C. However, when Fuzi was administered with Gancao, the metabolic profiles became similar to controls, whereby Gancao reduced the levels of trimethylamine N-oxide, betaine, dimethylglycine, valine, acetoacetate, citrate, fumarate, 2-ketoglutarate and hippurate, and regulated the concentrations of taurine and 3-hydroxybutyrate, resulting in a decrease in toxicity. Furthermore, important pathways that are known to be involved in the effect of Gancao on Fuzi, including phenylalanine, tyrosine and tryptophan biosynthesis, the synthesis and degradation of ketone bodies, and the TCA cycle, were altered in co-treated rats. CONCLUSIONS: Gancao treatment mitigated the metabolic changes altered by Fuzi administration in rats, demonstrating that dosing with Gancao could reduce the toxicity of Fuzi at the metabolic level. Fuzi and Gancao administered simultaneously resulted in improved toxicity reduction than when Gancao was administrated 5h prior to Fuzi. In summary, co-administration of Gancao with Fuzi reduces toxicity at the metabolic level.