Nephrotoxicity and carcinogenesis of aristolochic acids and their derivates

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Abstract

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.

Most cited references 59

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Aristolochic acid-associated urothelial cancer in Taiwan.

Dmitri Gnatenko, Kathleen G Dickman, Fe-Lin Wu … (2012)

Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of (5')AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.

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Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia

Steven G Rozen, Willie Yu, Yuka Suzuki … (2017)

Many traditional pharmacopeias include Aristolochia and related plants, which contain nephrotoxins and mutagens in the form of aristolochic acids and similar compounds (collectively, AA). AA is implicated in multiple cancer types, sometimes with very high mutational burdens, especially in upper tract urothelial cancers (UTUCs). AA-associated kidney failure and UTUCs are prevalent in Taiwan, but AA’s role in hepatocellular carcinomas (HCCs) there remains unexplored. Therefore, we sequenced the whole exomes of 98 HCCs from two hospitals in Taiwan and found that 78% showed the distinctive mutational signature of AA exposure, accounting for most of the nonsilent mutations in known cancer driver genes. We then searched for the AA signature in 1400 HCCs from diverse geographic regions. Consistent with exposure through known herbal medicines, 47% of Chinese HCCs showed the signature, albeit with lower mutation loads than in Taiwan. In addition, 29% of HCCs from Southeast Asia showed the signature. The AA signature was also detected in 13 and 2.7% of HCCs from Korea and Japan as well as in 4.8 and 1.7% of HCCs from North America and Europe, respectively, excluding one U.S. hospital where 22% of 87 "Asian" HCCs had the signature. Thus, AA exposure is geographically widespread. Asia, especially Taiwan, appears to be much more extensively affected, which is consistent with other evidence of patterns of AA exposure. We propose that additional measures aimed at primary prevention through avoidance of AA exposure and investigation of possible approaches to secondary prevention are warranted.

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Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation.

Agnieszka Pozdzik, C Decaestecker, Monique Deschodt-Lanckman … (2008)

Aristolochic acid contamination in herbal remedies leads to interstitial fibrosis, tubular atrophy, and renal failure in humans. To study the cellular mechanisms contributing to the pathophysiology of this renal disease, we studied Wistar rats treated with aristolochic acid and measured tubular and interstitial cell proliferation, epithelial/mesenchymal cell marker expression, tubular membrane integrity, myofibroblast accumulation, oxidative stress, mitochondrial damage, tubular apoptosis, and fibrosis. Oxidative stress, a loss of cadherin concomitant with vimentin expression, basement membrane denudation with active caspase-3 expression, and mitochondrial injury within tubular cells were evident within 5 days of administration of the toxin. During the chronic phase, interstitial mesenchymal cells accumulated in areas of collagen deposits. Impaired regeneration and apoptosis of proximal tubular cells resulted in tubule atrophy with a near absence of dedifferentiated cell transmembrane migration. We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during aristolochic acid toxicity.

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Author and article information

Contributors

Wu Xiong-Zhi

Journal

Journal ID (nlm-ta): TMR Editorial Board

Title: Traditional Medicine Research

Publisher: TMR Editorial Board (Jintang road, 99, Hedong district Tianjin,China, 300170 )

ISSN (Electronic): 2413-3973

Publication date Collection: January 2018

Publication date (Electronic): 20 January 2018

Volume: 3

Issue: 1

Pages: 1-9

Affiliations

[1-2413-3973-3-1-1] ¹Tianjin Medical University, School of Basic Medical Sciences, Department of Pharmacology, Tianjin, China.

[2-2413-3973-3-1-1] ²Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Author notes

^*Correspondence to: Xiong-Zhi Wu, Huan-Hu-Xi Road, He-Xi District, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. E-mail: wuxiongzhi@ 123456163.com.

Article

Publisher ID: 2413-3973-3-1-1

DOI: 10.12032/TMR201809059

SO-VID: d5dfd401-163f-4538-a14d-c1c38132e7ac

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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date accepted : 26 December 2017

Nephrotoxicity and carcinogenesis of aristolochic acids and their derivates

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Abstract

Most cited references 59

Aristolochic acid-associated urothelial cancer in Taiwan.

Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia

Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation.

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