Please wait a minute...
Traditional Medicine Research  2018, Vol. 3 Issue (1): 1-9    DOI: 10.12032/TMR201809059
Modernization of Traditional Medicine     
Nephrotoxicity and carcinogenesis of aristolochic acids and their derivates
Zi-Qi Jin1, Jin-Wei Yuan1, Jian Hao2, Xiong-Zhi Wu2,*()
1Tianjin Medical University, School of Basic Medical Sciences, Department of Pharmacology, Tianjin, China.
2Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Download: HTML     PDF(563KB)
Export: BibTeX | EndNote (RIS)      


This review summarized the toxicity and carcinogenesis of aristolochic acids and the underlying mechanisms.

Editor’s Summary

The mutational signature of aristolochic acids is related to the occurrence of HCC. However, the frequency of administration and dose, exposure time to aristolochic acids, and infectious situations of hepatitis B virus should also be further identified.


Aristolochic acids (AAs), a natural mixture of 8-methoxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAI) and 6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAII), derived from aristolochiaceae species, has been reported to cause AAS-induced nephropathy and upper urothelial cancer. In this review, we summarize the information on the nephrotoxicity and carcinogenesis of AAs and their derivatives. AAs nephrotoxicity can lead to apoptosis and oxidative stress of renal tubular cells, and inhibition of the expression of aquaporins. AAs can also reduce the capability for renal tubular epithelial cell repair after acute injury and further produce renal fibrosis by activating TGF-β-Smad signaling and promoting the migration of macrophages. Moreover, AAs-induced carcinogenesis may be due to the formation of covalent adducts with DNA which can lead to the mutation in certain tumor suppressor genes or proto-oncogenes and the different catalyzing capacity of the microsomal cytochrome P450 of individuals in AAI metabolism.

Key wordsAristolochic acids      Aristolochic acids nephropathy      Nephrotoxicity      Carcinogenesis     
Published: 05 January 2018
Corresponding Authors: Wu Xiong-Zhi     E-mail:
E-mail this article
Add to my bookshelf
Add to citation manager
E-mail Alert
Articles by authors
Jin Zi-Qi
Yuan Jin-Wei
Hao Jian
Wu Xiong-Zhi
Related Articles
No related articles found!
Cite this article:

Zi-Qi Jin, Jin-Wei Yuan, Jian Hao, Xiong-Zhi Wu. Nephrotoxicity and carcinogenesis of aristolochic acids and their derivates. Traditional Medicine Research, 2018, 3(1): 1-9. doi: 10.12032/TMR201809059

URL:     OR

Chinese medicine name Latin name
Dayeqingmuxiang Aristolochia austrozechuanica
Dabaijie Aristolochia chuii
Zhushalian Aristolochia cinnabarina
Aristolochia tuberosa
Jiuyuesheng (Zhushalian) Aristolochia Tuberosa C. F. Liang et S.M
Tianxianteng Aristolochia contorta
Aristolochia debilis
Madouling Aristolochia contorta
Aristolochia debilis
Fangji Aristolochia heterophylla
Aristolochia austrozechuanica
Aristolochia moupinensis
Hanfangji Aristolochia heterophylla
Huaitong Aristolochia moupinensis
Mufangji (Shuichengmufangji) Aristolochia moupinensis
Aristolochia ovatifatia
Muxiangmadouling Aristolochia moupinensis
Aristolochia griffithii Yhoms ex Duchartre
Daqingmuxiang Aristolochia kwangsiensis Chun et How
Mianningfangji Aristolochia moupinensis Franch
Xungufeng Aristolochia mollissima
Tiaoyexixin Asarum caudigerellum C.Y.Cheng
Asarum caudigerum Hance
Asarumsplendens (Maekawa) C.Y.Cheng et C.S.Yang
Asarum caulescens Maxim.
Wujinqi Asarum caulescens Maxim.
Duheng Asarum forbesii Maxim.
Asarum ichangense C.Y.Cheng et C.S.Yang
Xiangxixin Asarum forbesii Maxim.
Asarum ichangense C.Y.Cheng et C.S.Yang
Asarum wulingense C.F.Liang
Xixin Asarum heterotropoides Fr. Schmidt var. mandshuricum (Maxim.) Kitag.
Asarum sieboldii Miq.var.seoulense Nakai
Asarum sieboldii Miq
Gansuxixin Asarumhimalaicum Hook. f. et Thoms. ex Klotzsch
Nanpingxixin Asarumhimalaicum Hook. f. et Thoms. ex Klotzsch
Maoxixin Asarumhimalaicum Hook. f. et Thoms. ex Klotzsch
Jinerhuan Asarum insigne Diels
Shancigu Asarum sagittarioides C. F. Liang
Table 1 Chinese medicine known or suspected to contain aristolochic acids
Names Corresponding herbs containing aristolochic acids
Longdanxiegan pills Mutong
(Caulis Clematis Armanoii)
Fukefenqing pills Mutong
(Caulis Clematis Armanoii)
Ganluxiaodu pills Mutong
(Caulis Clematis Armanoii)
chuanbei powder
Madouling (Aristolochia debilis)
Jiming pills Madouling (Aristolochia debilis)
Qingguozhike pills Madouling (Aristolochia debilis)
Chuanxiling capsules Madouling (Aristolochia debilis)
Fei’an pills Madouling (Aristolochia debilis)
Qishiweisongshi pills Madouling (Aristolochia debilis)
Weifu granule Madouling (Aristolochia debilis)
Xiaoerzhike oral liquid Madouling (Aristolochia debilis)
Zhikehuatan pills Madouling (Aristolochia debilis)
Xiaokepingchuan oral liquid Madouling (Aristolochia debilis)
Zhikehuatan capsules Muxiangmadouling (Aristolochia ovatifatia)
Fengshisailong capsules Muxiangmadouling (Aristolochia ovatifatia)
Fengshizhitong pills Muxiangmadouling (Aristolochia ovatifatia)
Shuganliqi pills Qingmuxiang
(Aristolochia debilis)
Tianxianteng powder Tianxianteng
(Aristolochia contorta)
Heweijiangni capsules Tianxianteng
(Aristolochia contorta)
Dangguisini decoration Duheng
(Asarum forbesii Maxim.)
Baowei capsules Zhushalian
(Aristolochia cinnabarina)
Fufangweitong capsules Zhushalian
(Aristolochia cinnabarina)
Zhushalian capsules Zhushalian
(Aristolochia cinnabarina)
Fufangquancan tablets Xungufeng
(Aristolochia mollissima)
Shennong liquor Xungufeng
(Aristolochia mollissima)
Duzhongzhuanggu pills Xungufeng (Aristolochia mollissima)
Qufengchushi medicinal liquor Xungufeng
(Aristolochia mollissima)
Sanshe medicinal liquor Xungufeng
(Aristolochia mollissima)
Table 2 Chinese materia medica preparation containing aristolochic acids
Figure 1 Chemical structures of aristolochic acids and aristolactams
Items Mechanisms
Nephrotoxicity Apoptosis Increased intracellular Ca2+ concentration [11]
Mitochondria injury [12]
Inhibiting Akt and ERK1/2 [13, 14]
Activating of P53 [15]
Inducing a caspase 3-dependent pathway [16]
Oxidative stress Generation of reactive oxygen and nitrogen species [17, 18]
Aquaporins Inhibiting the expression of aquaporins [25]
Renal fibrosis Activating TGF-β-Smad signal [27, 35]
Promoting Macrophage migration [36, 37]
Carcinogenic Formation of AL adducts with DNA [44]
Gene mutation including lacZ, cll ,TP53 and H-RAS [50, 52]
Different activity of microsomal cytochrome P450 [57]
Increase the level of C-myc and Lin28B as well as G protein-coupled receptor 87 [58, 59]
Table 3 The mechanisms of nephrotoxicity and carcinogenesis of aristolochic acids
1.   Vanherweghem JL.Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium (Chinese herbs nephropathy). J Altern Complement Med 1998, 4: 9-13.
doi: 10.1089/acm.1998.4.1-9 pmid: 9553830
2.   Bhattacharjee P, Bera I, Chakraborty S, et al.Aristolochic acid and its derivatives as inhibitors of snake venom L-amino acid oxidase. Toxicon 2017, 138: 1-17.
doi: 10.1016/j.toxicon.2017.08.003
3.   Grollman AP.Aristolochic acid nephropathy: Harbinger of a global iatrogenic disease. Environ Mol Mutagen 2013, 54: 1-7.
doi: 10.1002/em.21756 pmid: 23238808
4.   Schmeiser HH, Kucab JE, Arlt VM, et al.Evidence of exposure to aristolochic acid in patients with urothelial cancer from a Balkan endemic nephropathy region of Romania. Environ Mol Mutagen 2012, 53: 636-641.
doi: 10.1002/em.21732 pmid: 22987305
5.   Ng AWT, Poon SL, Huang MN, et al. Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia. Sci Transl Med 2017, 9: eaan6446.
doi: 10.1126/scitranslmed.aan6446 pmid: 29046434
6.   Brown AC.Kidney toxicity related to herbs and dietary supplements: Online table of case reports. Part 3 of 5 series. Food Chem Toxicol 2017, 107: 502-519.
doi: 10.1016/j.fct.2016.07.024 pmid: 28755953
7.   Schmeiser HH, Pool BL, Wiessler M.Mutagenicity of the two main components of commercially available carcinogenic aristolochic acid in Salmonella typhimurium. Cancer Lett 1984, 23: 97-101.
doi: 10.1016/0304-3835(84)90067-3 pmid: 6378360
8.   Shibutani S, Dong H, Suzuki N, et al.Selective toxicity of aristolochic acids I and II. Drug Metab Dispos 2007, 35: 1217-1222.
doi: 10.1124/dmd.107.014688 pmid: 17392392
9.   Chang SY, Weber EJ, Sidorenko VS, et al.Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight 2017, 2: 95978.
doi: 10.1172/jci.insight.95978 pmid: 29202460
10.   Pozdzik AA, Salmon IJ, Debelle FD, et al.Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation. Kidney Int 2008, 73: 595-607.
doi: 10.1038/ pmid: 18094681
11.   Hsin YH, Cheng CH, Tzen JTC, et al.Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells. Apoptosis 2006, 11: 2167-2177.
doi: 10.1007/s10495-006-0289-0 pmid: 17051328
12.   Liu X, Wu J, Wang J, et al.Possible role of mitochondrial injury in Caulis Aristolochia manshuriensis-induced chronic aristolochic acid nephropathy. Drug Chem Toxicol 2017, 40: 115-124.
doi: 10.1080/01480545.2016.1188303
13.   Kwak DH, Lee S.Aristolochic acid I causes testis toxicity by inhibiting Akt and ERK1/2 phosphorylation. Chem Res Toxicol 2015, 29: 117-124.
doi: 10.1021/acs.chemrestox.5b00467 pmid: 26656393
14.   Romanov V, Whyard TC, Waltzer WC, et al.Aristolochic acid-induced apoptosis and G2 cell cycle arrest depends on ROS generation and MAP kinases activation. Arch Toxicol 2015, 89: 47-56.
doi: 10.1007/s00204-014-1249-z pmid: 24792323
15.   Zhou L, Fu P, Huang XR, et al.Activation of p53 promotes renal injury in acute aristolochic acid nephropathy. J Am Soc Nephrol 2010, 21: 31-41.
doi: 10.1681/ASN.2008111133 pmid: 19892935
16.   Li J, Zhang L, Jiang Z, et al.Toxicities of aristolochic acid I and aristololactam I in cultured renal epithelial cells. Toxicol Vitro 2010, 24: 1092-1097.
doi: 10.1016/j.tiv.2010.03.012 pmid: 20338233
17.   Wu TK, Wei CW, Pan YR, et al.Vitamin C attenuates the toxic effect of aristolochic acid on renal tubular cells via decreasing oxidative stress?mediated cell death pathways. Mol Med Rep 2015, 12: 6086-6092.
doi: 10.3892/mmr.2015.4167 pmid: 26239057
18.   Zhu S, Wang Y, Jin J, et al.Endoplasmic reticulum stress mediates aristolochic acid I-induced apoptosis in human renal proximal tubular epithelial cells. Toxicol Vitro 2012, 26: 663-671.
doi: 10.1016/j.tiv.2012.03.005 pmid: 22445861
19.   Wu TK, Pan YR, Wang HF, et al.Vitamin E (α?tocopherol) ameliorates aristolochic acid?induced renal tubular epithelial cell death by attenuating oxidative stress and caspase?3 activation. Mol Med Rep 2018, 17: 31-36.
doi: 10.3892/mmr.2017.7921 pmid: 29115579
20.   Knepper MA, Wade JB, Terris J, et al.Renal aquaporins. Kidney international 1996, 49: 1712-1717.
doi: 10.1038/ki.1996.253
21.   Yeum CH, Kim SW, Lee SC, et al.Diminished expression of aquaporin water channels in ureteral-obstructed kidney in rats. Scand J Urol Nephrol 2003, 37: 99-105.
doi: 10.1080/00365590310008811 pmid: 12745716
22.   Kortenoeven MLA, Fenton RA.Renal aquaporins and water balance disorders. Biochim Biophys Acta 2014, 1840: 1533-1549.
doi: 10.1016/j.beem.2016.02.012 pmid: 27156764
23.   Li J, Zhang L, Jiang ZZ, et al.Expression of renal aquaporins in aristolochic acid I and aristolactam I-induced nephrotoxicity. Nephron 2016, 133: 213-221.
doi: 10.1159/000446854 pmid: 27352112
24.   Kwon TH, Fr?ki?r J, Nielsen S.Regulation of aquaporin-2 in the kidney: a molecular mechanism of body-water homeostasis. Kidney Res Clin Pract 2013, 32: 96-102.
doi: 10.1016/j.krcp.2013.07.005 pmid: 26877923
25.   Li J, Zhang L, Jiang ZZ, et al.Expression of renal aquaporins in aristolochic acid I and aristolactam I-induced nephrotoxicity. Nephron 2016, 133: 213-221.
doi: 10.1159/000446854 pmid: 27352112
26.   Kaissling B, LeHir M, Kriz W. Renal epithelial injury and fibrosis. Biochim Biophys Acta 2013, 1832: 931-939.
doi: 10.1016/j.bbadis.2013.02.010 pmid: 23466594
27.   Yang L, Li X, Wang H.Possible mechanisms explaining the tendency towards interstitial fibrosis in aristolochic acid-induced acute tubular necrosis. Nephrol Dial Transplant 2006, 22: 445-456.
doi: 10.1093/ndt/gfl556 pmid: 17124284
28.   Hugo C, Daniel C.Thrombospondin in renal disease. Nephron Exp Nephrol 2009, 111: e61-e66.
doi: 10.1159/000198235
29.   Lu A, Miao M, Schoeb TR, et al.Blockade of TSP1-dependent TGF-β activity reduces renal injury and proteinuria in a murine model of diabetic nephropathy. Am J Pathol 2011, 178: 2573-2586.
doi: 10.1016/j.ajpath.2011.02.039 pmid: 21641382
30.   Daniel C, Wiede J, Krutzsch HC, et al.Thrombospondin-1 is a major activator of TGF-β in fibrotic renal disease in the rat in vivo. Kidney Int 2004, 65: 459-468.
doi: 10.1111/j.1523-1755.2004.00395.x pmid: 14717916
31.   Lu H, Chen B, Hong W, et al.Transforming growth factor-β1 stimulates hedgehog signaling to promote epithelial-mesenchymal transition after kidney injury. FEBS J 2016, 283: 3771-3790.
doi: 10.1111/febs.2016.283.issue-20
32.   Pozdzik AA, Giordano L, Li G, et al.Blocking TGF-β signaling pathway preserves mitochondrial proteostasis and reduces early activation of PDGFRβ+ pericytes in aristolochic acid induced acute kidney injury in wistar male rats. PloS One 2016, 11: e0157288.
doi: 10.1371/journal.pone.0157288 pmid: 27379382
33.   Sun D, Feng J, Dai C, et al.Role of peritubular capillary loss and hypoxia in progressive tubulointerstitial fibrosis in a rat model of aristolochic acid nephropathy. Am J Nephrol 2006, 26: 363-371.
doi: 10.1159/000094778 pmid: 16873992
34.   Wang Z, Zhao J, Zhang J, et al.Protective effect of BMP-7 against aristolochic acid-induced renal tubular epithelial cell injury. Toxicol Lett 2010, 198: 348-357.
doi: 10.1016/j.toxlet.2010.07.018 pmid: 20696222
35.   Zeniya M, Mori T, Yui N, et al.The proteasome inhibitor bortezomib attenuates renal fibrosis in mice via the suppression of TGF-β1. Sci Rep 2017, 7: 13086.
doi: 10.1038/s41598-017-13486-x pmid: 29026167
36.   Dai XY, Huang XR, Zhou L, et al.Targeting c-fms kinase attenuates chronic aristolochic acid nephropathy in mice. Oncotarget 2016, 7: 10841.
doi: 10.18632/oncotarget.7460 pmid: 26909597
37.   Lu H, Bai Y, Wu L, et al.Inhibition of macrophage migration inhibitory factor protects against inflammation and matrix deposition in kidney tissues after injury. Mediators Inflamm 2016, 2016:1-12.
doi: 10.1155/2016/2174682 pmid: 27313397
38.   Chen CH, Dickman KG, Moriya M, et al.Aristolochic acid-associated urothelial cancer in Taiwan. Proc Natl Acad Sci 2012, 109: 8241-8246.
doi: 10.1073/pnas.1119920109 pmid: 22493262
39.   Jelakovi? B, Karanovi? S, Vukovi?-Lela I, et al.Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid. Kidney Int 2012, 81: 559-567.
doi: 10.1038/ki.2011.371 pmid: 22071594
40.   Hoang ML, Chen CH, Chen PC, et al.Aristolochic acid in the etiology of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev 2016, 25: 1600-1608.
doi: 10.1158/1055-9965.EPI-16-0219 pmid: 27555084
41.   Jin K, Su K, Li T, et al.Hepatic premalignant alterations triggered by human nephrotoxin aristolochic acid I in canines. Cancer Prev Res 2016, 9: 324-334.
doi: 10.1158/1940-6207.CAPR-15-0339 pmid: 26851235
42.   Mei N, Arlt VM, Phillips DH, et al.DNA adduct formation and mutation induction by aristolochic acid in rat kidney and liver. Mutat Res 2006, 602: 83-91.
doi: 10.1016/j.mrfmmm.2006.08.004 pmid: 17010389
43.   Bara JR T, Gurzu S, Sugimura H, et al.A systematic review of the possible carcinogenic role of the aristolochic acid. Rom J Morphol Embryol 2017, 58: 41-44.
pmid: 28523296
44.   Jelakovi? B, Karanovi? S, Vukovi?-Lela I, et al.Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid. Kidney Int, 2012, 81: 559-567.
doi: 10.1038/ki.2011.371 pmid: 22071594
45.   Krumbiegel G, Hallensleben J, Mennicke WH, et al.Studies on the metabolism of aristolochic acids I and II. Xenobiotica 1987, 17: 981-991.
doi: 10.3109/00498258709044197 pmid: 3673113
46.   Chan W, Cui L, Xu G, et al.Study of the phase I and phase II metabolism of nephrotoxin aristolochic acid by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2006, 20: 1755-1760.
doi: 10.1002/rcm.2513 pmid: 16676316
47.   Pfau W, Schmeiser HH, Wiessler M.Aristolochic acid binds covalently to the exocyclic amino group of purine nucleotides in DNA. Carcinog 1990, 11: 313-319.
doi: 10.1093/carcin/11.2.313 pmid: 2302759
48.   Pfau W, Schmeiser HH, Wiessler M.32P- postlabelling analysis of the DNA adducts formed by aristolochic acid I and II. Carcinog 1990, 11: 1627-1633.
doi: 10.1093/carcin/11.9.1627
49.   Maier P, Schawalder HP, Weibel B, et al.Aristolochic acid induces 6-thioguanine-resistant mutants in an extrahepatic tissue in rats after oral application. Mutat Res 1985, 143: 143-148.
doi: 10.1016/S0165-7992(85)80025-7 pmid: 4010694
50.   Kohara A, Suzuki T, Honma M, et al.Mutagenicity of aristolochic acid in the lambda/lacZ transgenic mouse (Muta? Mouse). Mutat Res Genet Toxicol Environ Mutagen 2002, 515: 63-72.
doi: 10.1016/S1383-5718(01)00350-3 pmid: 11909755
51.   Ding YJ, Chen YH.Developmental nephrotoxicity of aristolochic acid in a zebrafish model. Toxicol Appl Pharmacol 2012, 261: 59-65.
doi: 10.1016/j.taap.2012.03.011 pmid: 22472514
52.   Nedelko T, Arlt VM, Phillips DH, et al.TP53 mutation signature supports involvement of aristolochic acid in the aetiology of endemic nephropathy-associated tumours. Int J Cancer 2009, 124: 987-990.
doi: 10.1002/ijc.24006 pmid: 19030178
53.   Rosenquist TA, Grollman AP.Mutational signature of aristolochic acid: Clue to the recognition of a global disease. DNA repair 2016, 44: 205-211.
doi: 10.1016/j.dnarep.2016.05.027 pmid: 27237586
54.   Stiborová M, Arlt VM, Schmeiser HH.Balkan endemic nephropathy: an update on its aetiology. Arch Toxicol 2016, 90: 2595-2615.
doi: 10.1007/s00204-016-1819-3 pmid: 5065591
55.   Schmeiser HH, Nortier JL, Singh R, et al.Exceptionally long-term persistence of DNA adducts formed by carcinogenic aristolochic acid I in renal tissue from patients with aristolochic acid nephropathy. Int J Cancer 2014, 135: 502-507.
doi: 10.1002/ijc.28681 pmid: 24921086
56.   NTP (National Toxicology Program). 2016. Report on Carcinogens, Fourteenth Edition. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service. .
57.   Dra?ínská H, Bárta F, Levová K, et al.Induction of cytochromes P450 1A1 and 1A2 suppresses formation of DNA adducts by carcinogenic aristolochic acid I in rats in vivo. Toxicol 2016, 344: 7-18.
doi: 10.1016/j.tox.2016.01.011 pmid: 26845733
58.   Jin K, Su K, Li T, et al.Hepatic premalignant alterations triggered by human nephrotoxin aristolochic acid I in canines. Cancer Prev Res 2016, 9: 324-334.
doi: 10.1158/1940-6207.CAPR-15-0339 pmid: 26851235
59.   Lin CE, Chang WS, Lee JA, et al.Proteomics analysis of altered proteins in kidney of mice with aristolochic acid nephropathy using the fluorogenic derivatization-liquid chromatography-tandem mass spectrometry method. Biomed Chromatogr 2017: e4127.
doi: 10.1002/bmc.4127 pmid: 29088495
60.   Shi M, Ma L, Zhou L, et al.Renal protective effects of 17β-estradiol on mice with acute aristolochic acid nephropathy. Molecules 2016, 21: 1391.
doi: 10.3390/molecules21101391 pmid: 27763560
61.   Declèves A é, Jadot I, Colombaro V, et al.Protective effect of nitric oxide in aristolochic acid-induced toxic acute kidney injury: an old friend with new assets. Exp Physiol 2016, 101: 193-206.
doi: 10.1113/EP085333 pmid: 26442795
62.   Hamano Y, Aoki T, Shirai R, et al.Low-dose darbepoetin α attenuates progression of a mouse model of aristolochic acid nephropathy through early tubular protection. Nephron Exp Nephrol 2010, 114: e69-e81.
doi: 10.1159/000256569 pmid: 19907192
63.   Wang K, Feng C, Li C, et al.Baicalin protects mice from aristolochic acid I-induced kidney injury by induction of CYP1A through the aromatic hydrocarbon receptor. Int J Mol Sci 2015, 16: 16454-16468.
doi: 10.3390/ijms160716454
No related articles found!