Search JIM Advanced Search

Journal of Chinese Integrative Medicine ›› 2009, Vol. 7 ›› Issue (8): 746-752.doi: 10.3736/jcim20090808

• Original Experimental Research • Previous Articles     Next Articles

Nephrotoxicity study of Aristolochia fangchi in rats by metabonomics

Qi Lianga,Cheng Nia,Ming Xiea,Qi Zhangb,Yan-xia Zhanga,Xian-zhong Yanb,Mei-juan Yanga,Shuang-qing Penga   

  1. a Department of Formulaology, Beijing University of Chinese Medicine, Beijing 100029, China
    b National Center of Biomedical Analysis,Beijing 100850,China
  • Received:2009-04-22 Accepted:2009-06-20 Online:2009-08-20 Published:2009-08-15
  • Contact: Ming Xie E-mail:xieming603@263.net

Objective

To study the changes of metabolites in rat urine after treatment of Aristolochia fangchi decoction by metabonomic method. 

Methods

Sixty-four male SD rats were divided into Aristolochia fangchi group and normal control group. Rats in the Aristolochia fangchi group were orally administered with 8.1 g/(kg·d) of Aristolochia fangchi and the normal control group was administered with equal volume of distilled water for 4 weeks. Twenty-four hour urine was collected at different time points (before, after 2- and 4-week administration and 2 weeks after administration) and their 1H nuclear magnetic resonance (NMR) spectra were acquired and subjected to data process, including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) or orthogonal signal correction (OSC). The contents of blood urea nitrogen (BUN) and serum creatinine (SCr) and histopathological changes of the renal tissues were also detected. Results

The content of BUN of the Aristolochia fangchi group was markedly higher than that of the normal control group after 2-week administration (P<0.05), and cellular edema in tubular endothelial cells, structure damage of glomeruli and inflammatory cell infiltration were found in the kidney. Along with the lasting of administration to 4-week, the renal injury in the Aristolochia fangchi group became more serious, and the contents of BUN and SCr were all significantly higher as compared with the normal control group (P<0.05). Two weeks after administration, the content of BUN in the Aristolochia fangchi group was still higher than that in the normal control group (P<0.05), and the pathological changes in renal tissues were not different from those on the 4th week. The urine of the Aristolochia fangchi group could be readily discriminated from the normal control group at every time point based on PCA. During the whole administration period, compared with the normal control group, the concentration of urinary taurine was increased time-dependently, while the citrate was decreased in the Aristolochia fangchi group. The concentration of hippurate was increased at the 2nd week and the 6th week (2 weeks after drug withdrawal) but decreased at the 4th week; the concentration of creatinine/creatine was increased at the 4th week but decreased at the 6th week; the concentration of 2-oxo-glutarate was decreased and the concentration of trimethylamine oxide was increased at the 4th and 6th week.
Conclusion

High-dose Aristolochia fangchi can induce renal lesion and its seriousness is correspondent to the lasting of administration. Aristolochia fangchi may also have toxicity on liver.

Key words: Aristolochia fangchi, Nephrotoxicity, Metabonomics, Nuclear magnetic resonance, Pattern recognition, Rats

Table 1

Contents of BUN and SCr of rats in two groups on different time-points ($\bar{x}$±s, mmol/L)"

Group n BUN SCr
Normal control
Before treatment 8 4.12±0.42 30.20±4.32
After 2-week treatment 8 6.30±0.33 41.80±5.81
After 4-week treatment 8 5.58±1.06 50.40±4.83
2 weeks after treatment 8 5.82±0.65 56.40±3.78
Aristolochia fangchi
Before treatment 8 4.12±0.42 30.20±4.32
After 2-week treatment 8 7.58±0.80* 37.25±3.24
After 4-week treatment 8 13.67±2.18** 80.63±13.78**
2 weeks after treatment 8 13.63±1.44** 65.25±12.36

Figure 1

Renal histopathological changes of rats at different time-points (HE staining, ×400) A: Normal control group; B: Aristolochia fangchi group, after 2-week administration; C: Aristolochia fangchi group, after 4-week administration; D: Aristolochia fangchi group, 2 weeks after administration."

Figure 2

1H NMR spectra of rats treated with Aristolochia fangchi after different treatment days a: Before administration; b: After 2-week administration; c: After 4-week administration; d: Two weeks after administration."

Figure 3

Pattern recognition and corresponding loading plots of urine samples obtained from rats in normal control group and Aristolochia fangchi group A: PLS-DA score scatter and corresponding loading plots; B: PCA score scatter and corresponding loading plots; C: PCA score scatter and corresponding loading plots. Z: Normal control group; G: Aristolochia fangchi group; a: Before administration; b: After 2-week administration; c: After 4-week administration; d: Two weeks after administration."

[1] Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Dratwa M, Jadoul M, Richard C, Vandervelde D, Verbeelen D, Vanhaelen-Fastre R . Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs[J]. Lancet, 1993,341(8842):387-391
doi: 10.1016/0140-6736(93)92984-2
[2] Nicholson JK, Lindon JC, Holmes E . 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data[J]. Xenobiotica, 1999,29(11):1181-1189
doi: 10.1080/004982599238047
[3] Lindon JC, Holmes E, Nicholson JK . Pattern recognition methods and applications in biomedical magnetic resonance[J]. Prog NMRS, 2001,39(1):1-40
doi: 10.1016/S0079-6565(00)00036-4
[4] Nicholson JK, Connelly J, Lindon JC, Holmes E . Metabonomics: a platform for studying drug toxicity and gene function[J]. Nat Rev Drug Discov, 2002,1(2):153-161
doi: 10.1038/nrd728 pmid: 12120097
[5] Yang CS, Lin CH, Chang SH, Hsu HC . Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs[J]. Am J Kidney Dis, 2000,35(2):313-318
doi: 10.1016/S0272-6386(00)70343-X pmid: 10676733
[6] Holmes E, Connor SC, Nicholls AW, Nicholson JK, Lindon JC, Connor SC, Polley S, Connelly J . The identification of novel biomarkers of renal toxicity using automatic data reduction techniques and PCA of proton NMR spectra of urine[J]. Chemometri Intell Lab Sys, 1998,44(1):245-255
doi: 10.1016/S0169-7439(98)00110-5
[7] Xu B, Zhao YM . Changes of metabonomic profiles of rat urine after oral administration of Radix Gentianae decoction[J]. Zhongguo Yao Li Xue Yu Du Li Xue Za Zhi, 2008,22(3):221-226
doi: 10.3867/j.issn.1000-3002.2008.03.011
徐斌, 赵毅民 . 大鼠口服龙胆水煎剂后尿液代谢谱的变化[J]. 中国药理学与毒理学杂志, 2008,22(3):221-226
doi: 10.3867/j.issn.1000-3002.2008.03.011
[8] Nicholson JK, Timbrell JA, Sadler PJ . Proton NMR spectra of urine as indicators of renal damage. Mercury-induced nephrotoxicity in rats[J]. Mol Pharmacol, 1985,27(6):644-651
[9] Gartland KP, Bonner FW, Nicholson JK . Investigations into the biochemical effects of region-specific nephrotoxins[J]. Mol Pharmacol, 1989,35(2):242-250
pmid: 2918855
[10] Zhao JY, Yan XZ, Peng SQ . Studying nephrotoxicity of Aristolochia manshuriensis using metabonomics[J]. Shi Jie Ke Xue Ji Shu Zhong Yi Yao Xian Dai Hua, 2007,9(5):54-59, 148
赵剑宇, 颜贤忠, 彭双清 . 利用代谢组学技术研究中药关木通的肾毒性作用[J]. 世界科学技术: 中医药现代化, 2007,9(5):54-59, 148
[11] Friese J, Gleitz J, Gutser UT, Heubach JF, Matthiesen T, Wilffert B, Selve N . Aconitum sp. alkaloids: the modulation of voltage-dependent Na+ channels, toxicity and antinociceptive properties[J]. Eur J Pharmacol, 1997,337(2-3):165-174
doi: 10.1016/S0014-2999(97)01268-5
[12] Wang QJ, Yan XZ, Wu CQ, Zhao JY, Yu SZ, Yuan BL, Liao MY . A nuclear magnetic resonance spectroscopic metabonomics analysis for urine from rats admi-nistrated Z24 orally[J]. Zhongguo Yao Li Xue Yu Du Li Xue Za Zhi, 2004,18(6):460-465
王全军, 颜贤忠, 吴纯启, 赵剑宇, 余寿忠, 袁本利, 廖明阳 . Z24经口染毒大鼠尿液的核磁共振谱代谢组学研究[J]. 中国药理学与毒理学杂志, 2004,18(6):460-465
[13] Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ . Mechanisms of hepatotoxi-city[J]. Toxicol Sci, 2002,65(2):166-176
doi: 10.1093/toxsci/65.2.166
[14] Liao Y, Peng SQ, Yan XZ, Zhang LS . Metabonomics profile of urine from rats administrated with different treatment period of isoniazid[J]. Zhongguo Yi Xue Ke Xue Xue Bao, 2007,29(6):730-737
廖艳, 彭双清, 颜贤忠, 张立实 . 抗结核药物异烟肼肝毒性时效关系的代谢组学[J]. 中国医学科学学报, 2007,29(6):730-737
[15] Ni C . Study on the effect and toxicity of Aristolochiae fangchi, Stephania tetrandra and their combination with Astragali radix separately[M]. Beijing: Beijing University of Chinese Medicine, 2007
倪诚 . 广防己和粉防己及其配伍黄芪的效毒研究[M]. 北京: 北京中医药大学, 2007
[1] Surendra Kr. Sharma, Naveen Goyal. Protective effect of Heliotropium eichwaldi against cisplatin-induced nephrotoxicity in mice. Journal of Chinese Integrative Medicine, 2012, 10(5): 555-560.
[2] Hua-qiang Zhai, Shuo-feng Zhang, Ming-chao Gao, Yang Liu, Min Ou, Fan-yun Meng, Yong-yan Wang. Effects of Herba Ephedra Sinicae and Fructus Schisandrae Chinensis on pathology of rats with bleomycin A5-induced idiopathic pulmonary fibrosis. Journal of Chinese Integrative Medicine, 2011, 9(5): 553-557.
[3] Srinivas Ashok Kumar Bagepalli, Lakshman Kuruba, Avalakondarayppa Arun Kumar Peresandra, Lakshminarayana Shastry Viswantha Gollapalle, Prabhakar Veerapur Veeresh, Shivanadppa Thippeswamy Boreddy, Manoj Bachappa. Hepatoprotective activity of methanol extract of Amaranthus caudatus Linn. against paracetamol-induced hepatic injury in rats. Journal of Chinese Integrative Medicine, 2011, 9(2): 194-200.
[4] Wei-liang Gu, Chang-xun Chen, Ying Wang. Comparative study of Scrophulariae and Aconite in inhibiting myocardial hypertrophy in rats and mice. Journal of Chinese Integrative Medicine, 2008, 6(4): 376-380.
[5] Hui Li, Xiao-qing Liu, Bing Zhang, Li Ni, Zhi-jian Ling. Effects of active component in Cichorii on lipid metabolism of rat with hypertriglyceridemia complicated by hyperuricemia and hyperglycemia. Journal of Chinese Integrative Medicine, 2008, 6(2): 157-162.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
[1] Dong Yang, Yong-ping Du, Qing Shen, Wei Chen, Yan Yu, Guang-lei Chen. Expression of alpha-smooth muscle actin in renal tubulointerstitium in patients with kidney collateral stasis. Journal of Chinese Integrative Medicine, 2008, 6(1): 41-44
[2] Nian-hong Wang , Jun-tao Yan , Wu-quan Sun , Yong-shan Hu , Jun Xia , Li-cheng Wei , Jie Jia , Gui-lin Ouyang , Yong He , Yan-ming Guo , Jie Xu . Effects of early application of Tuina treatment on quadriceps surface myoelectricity in patients after total knee arthroplasty: a randomized controlled trial. Journal of Chinese Integrative Medicine, 2012, 10(11): 1247-1253
[3] Zhao-guo Li, Gang Chen. Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: Six-meridian Pattern Identification/Syndrome Differentiation. Journal of Chinese Integrative Medicine, 2011, 9(11): 1270-1276
[4] Yong-mei Liu, Rui-hua Liu, Wen-jun Liu, Li Liu , Zhi-kui Wu, Yu-ying Chen. Effects of Chinese herbal medicine Yiqi Huoxue Formula on TGF-p/smad signal transduction pathway and connective tissue growth factor in rats with renal interstitial fibrosis. Journal of Chinese Integrative Medicine, 2010, 8(12): 1165-1173
[5] Hui Li, Xiao-qing Liu, Bing Zhang, Li Ni, Zhi-jian Ling. Effects of active component in Cichorii on lipid metabolism of rat with hypertriglyceridemia complicated by hyperuricemia and hyperglycemia. Journal of Chinese Integrative Medicine, 2008, 6(2): 157-162
[6] Qing-hui Zhou, Chang-quan Ling, Yu-jin Bai, Hui-xia Yin. Journal selection and indexing for Index Medicus and Chinese periodicals indexed in Index Medicus. Journal of Chinese Integrative Medicine, 2005, 3(1): 70-77
[7] Tao Li-li, Lei Yan. Effects of extracts from Panax ginseng, Panax notoginseng and Ligusticum chuanxiong on expression of β-galactosidase and signal pathway p16-cyclin D/CDK-Rb in vascular smooth muscle cells. Journal of Chinese Integrative Medicine, 2012, 10(1): 76-84
[8] Vamsi Reddy, Arvind Sridhar, Roberto F. Machado, Jiwang Chen. High sodium causes hypertension: Evidence from clinical trials and animal experiments. Journal of Integrative Medicine, 2015, 13(1): 1-8
[9] Yong-qing Cao, Chun-mei He, Jin-gen Lu. Effects of Wenshen Jianpi Recipe on chronic wound healing in rats. Journal of Chinese Integrative Medicine, 2005, 3(3): 220-223
[10] Xiao-ning Wang, Yi-yang Hu, Cheng-hai Liu, Ping Liu, Da-yuan Zhu. Effects of salvianolic acid B on expressions of TGF-β1 and its receptors in liver of rats with dimethylnitrosamine-induced hepatic fibrosis. Journal of Chinese Integrative Medicine, 2005, 3(4): 286-288