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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.
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Highlights

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.

Abstract

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: wuxiongzhi@163.com.
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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

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https://www.tmrjournals.com/tmr/EN/10.12032/TMR201809059     OR     https://www.tmrjournals.com/tmr/EN/Y2018/V3/I1/1

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)
Fufangshedan
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
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