Aristolochic acid (AA) is a plant alkaloid that causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases frequently associated with upper urothelial cancer (UUC). This review summarizes the significance of AA-derived DNA adducts in the aetiology of UUC leading to specific A:T to T:A transversion mutations (mutational signature) in AAN/BEN-associated tumours, which are otherwise rare in individuals with UCC not exposed to AA. Therefore, such DNA damage produced by AA-DNA adducts is one rare example of the direct association of exposure and cancer development (UUC) in humans, confirming that the covalent binding of carcinogens to DNA is causally related to tumourigenesis. Although aristolochic acid I (AAI), the major component of the natural plant extract AA, might directly cause interstitial nephropathy, enzymatic activation of AAI to reactive intermediates capable of binding to DNA is a necessary step leading to the formation of AA-DNA adducts and subsequently AA-induced malignant transformation. Therefore, AA-DNA adducts can not only be utilized as biomarkers for the assessment of AA exposure and markers of AA-induced UUC, but also be used for the mechanistic evaluation of its enzymatic activation and detoxification. Differences in AA metabolism might be one of the reasons for an individual's susceptibility in the multi-step process of AA carcinogenesis and studying associations between activities and/or polymorphisms of the enzymes metabolising AA is an important determinant to identify individuals having a high risk of developing AA-mediated UUC.

Analytical and Environmental Sciences Division MRC PHE Centre for Environment and Health King's College London London SE1 9NH UK

Department of Biochemistry Faculty of Science Charles University Albertov 2030 CZ 12843 Prague 2 Czech Republic

Division of Radiopharmaceutical Chemistry German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany

NIHR Health Protection Research Unit in Health Impact of Environmental Hazards at King's College London in partnership with Public Health England London SE1 9NH UK

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Poirier M. Chemical-induced DNA damage and human cancer risk. Nat. Rev. Cancer. 2004;4:630–637. doi: 10.1038/nrc1410. PubMed DOI

Poirier M.C. Chemical-induced DNA damage and human cancer risk. Discov. Med. 2012;14:283–288. doi: 10.1038/nrc1410. PubMed DOI PMC

Poirier M.C. Linking DNA adduct formation and human cancer risk in chemical carcinogenesis. Environ. Mol. Mutagen. 2016;57:499–507. doi: 10.1002/em.22030. PubMed DOI

Loeb L.A., Harris C.C. Advances in chemical carcinogenesis: A historical review and prospective. Cancer Res. 2008;68:6863–6872. doi: 10.1158/0008-5472.CAN-08-2852. PubMed DOI PMC

Guengerich F.P. Metabolism of chemical carcinogens. Carcinogenesis. 2000;21:345–351. doi: 10.1093/carcin/21.3.345. PubMed DOI

Phillips D.H. DNA adducts as markers of exposure and risk. Mutat. Res. 2005;577:284–292. doi: 10.1016/j.mrfmmm.2005.03.008. PubMed DOI

Phillips D.H. Cancer Handbook. Wiley; Hoboken, NJ, USA: 2007. The Formation of DNA Adducts.

Phillips D.H., Arlt V.M. Genotoxicity: Damage to DNA and its consequences. EXS. 2009;99:87–110. PubMed

Baird W.M., Hooven L.A., Mahadevan B. Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of action. Environ. Mol. Mutagen. 2005;45:106–114. doi: 10.1002/em.20095. PubMed DOI

Turesky R.J., le Marchand L. Metabolism and biomarkers of heterocyclic aromatic amines in molecular epidemiology studies: Lessons learned from aromatic amines. Chem. Res. Toxicol. 2011;24:1169–1214. doi: 10.1021/tx200135s. PubMed DOI PMC

Phillips D.H., Arlt V.M. The 32P-postlabeling assay for DNA adducts. Nat. Protoc. 2007;2:2772–2781. doi: 10.1038/nprot.2007.394. PubMed DOI

Phillips D.H., Venitt S. DNA and protein adducts in human tissues resulting from exposure to tobacco smoke. Int. J. Cancer. 2012;131:2733–2753. doi: 10.1002/ijc.27827. PubMed DOI

Rappaport S.M., Li H., Grigoryan H., Funk W.E., Williams E.R. Adductomics: Characterizing exposures to reactive electrophiles. Toxicol. Lett. 2012;213:83–90. doi: 10.1016/j.toxlet.2011.04.002. PubMed DOI PMC

Harris C.C. 1995 Deichmann Lecture—p53 tumor suppressor gene: At the crossroads of molecular carcinogenesis, molecular epidemiology and cancer risk assessment. Toxicol. Lett. 1995;82–83:1–7. doi: 10.1016/0378-4274(95)03643-1. PubMed DOI

Wogan G.N., Kensler T.W., Groopman J.D. Present and future directions of translational research on aflatoxin and hepatocellular carcinoma. A review. Food Addit. Contam. Part. A Chem. Anal. Control Expo. Risk Assess. 2012;29:249–257. doi: 10.1080/19440049.2011.563370. PubMed DOI PMC

Arlt V.M., Stiborova M., Schmeiser H.H. Aristolochic acid as a probable human cancer hazard in herbal remedies: A review. Mutagenesis. 2002;17:265–277. doi: 10.1093/mutage/17.4.265. PubMed DOI

Stiborova M., Frei E., Arlt V.M., Schmeiser H.H. The role of biotransformation enzymes in the development of renal injury and urothelial cancer caused by aristolochic acid: urgent questions and difficult answers. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2009;153:5–11. doi: 10.5507/bp.2009.001. PubMed DOI

Stiborová M., Frei E., Arlt V.M., Schmeiser H.H. Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy. Mutat. Res. 2008;658:55–67. doi: 10.1016/j.mrrev.2007.07.003. PubMed DOI

Stiborová M., Frei E., Schmeiser H.H. Biotransformation enzymes in development of renal injury and urothelial cancer caused by aristolochic acid. Kidney Int. 2008;73:1209–1211. doi: 10.1038/ki.2008.125. PubMed DOI

Stiborová M., Martínek V., Frei E., Arlt V.M., Schmeiser H.H. Enzymes metabolizing aristolochic acid and their contribution to the development of Aristolochic acid nephropathy and urothelial cancer. Curr. Drug Metab. 2013;14:695–705. doi: 10.2174/1389200211314060006. PubMed DOI

Stiborová M., Arlt V.M., Schmeiser H.H. Balkan endemic nephropathy: An update on its aetiology. Arch. Toxicol. 2016;90:2595–2615. doi: 10.1007/s00204-016-1819-3. PubMed DOI PMC

Schmeiser H.H., Stiborova M., Arlt V.M. Chemical and molecular basis of the carcinogenicity of Aristolochia plants. Curr. Opin. Drug Discov. Dev. 2009;12:141–148. PubMed

Gökmen M.R., Cosyns J.P., Arlt V.M., Stiborová M., Phillips D.H., Schmeiser H.H., Simmonds M.S.J., Look H.T., Vanherweghem J.L., Nortier J.L., et al. The epidemiology, diagnosis and management of Aristolochic Acid Nephropathy: A narrative review. Ann. Intern. Med. 2013;158:469–477. doi: 10.7326/0003-4819-158-6-201303190-00006. PubMed DOI

Grollman A.P. Aristolochic acid nephropathy: Harbinger of a global iatrogenic disease. Environ. Mol. Mutagen. 2013;54:1–7. doi: 10.1002/em.21756. PubMed DOI

Schmeiser H.H., Pool B.L., 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. PubMed DOI

Kohara A., Suzuki T., Honma M., Ohwada T., Hayashi M. Mutagenicity of aristolochic acid in the lambda/lacZ transgenic mouse (MutaMouse) Mutat. Res. 2002;515:63–72. doi: 10.1016/S1383-5718(01)00350-3. PubMed DOI

Nortier J.L., Martinez M.C., Schmeiser H.H., Arlt V.M., Bieler C.A., Petein M., Depierreux M.F., de Pauw L., Abramowicz D., Vereerstraeten P., et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi) N. Engl. J. Med. 2000;342:1686–1692. doi: 10.1056/NEJM200006083422301. PubMed DOI

Mei N., Arlt V.M., Phillips D.H., Heflich R.H., Chen T. 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. PubMed DOI PMC

International Agency for Research on Cancer (IARC) Environmental Health Criteria Monographs. World Health Organization; Geneva, Switzerland: 2012. A review of human CARCINOGENS: Pharmaceuticals.

Schmeiser H.H., Kucab J.E., Arlt V.M., Phillips D.H., Hollstein M., Gluhovschi G., Gluhovschi C., Modilca M., Daminescu L., Petrica L., 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. PubMed DOI

Hoang M.L., Chen C.H., Chen P.C., Roberts N.J., Dickman K.G., Yun B.H., Turesky R.J., Pu Y.S., Vogelstein B., Papadopoulos N., et al. Aristolochic acid in the etiology of renal cell carcinoma. Cancer Epidemiol. Biomark. Prev. 2016;25:1600–1608. doi: 10.1158/1055-9965.EPI-16-0219. PubMed DOI PMC

Rosenquist T.A., Grollman A.P. Mutational signature of aristolochic acid: Clue to the recognition of a global disease. DNA Repair. 2016;44:205–2011. doi: 10.1016/j.dnarep.2016.05.027. PubMed DOI

Vanherweghem J.L., Tielemans C., Abramowicz D., Depierreux M., Vanhaelen-Fastre R., Vanhaelen M., Dratwa M., Richard C., Vandervelde D., Verbeelen D., et al. Rapidly progressive interstitial renal fibrosis in young women: Association with slimming regimen including Chinese herbs. Lancet. 1993;341:387–391. doi: 10.1016/0140-6736(93)92984-2. PubMed DOI

Arlt V.M., Alunni-Perret V., Quatrehomme G., Ohayon P., Albano L., Gaïd H., Michiels J.F., Meyrier A., Cassuto E., Wiessler M., et al. Aristolochic acid (AA)-DNA adduct as marker of AA exposure and risk factor for AA nephropathy-associated cancer. Int. J. Cancer. 2004;111:977–980. doi: 10.1002/ijc.20316. PubMed DOI

Debelle F.D., Vanherweghem J.L., Nortier J.L. Aristolochic acid nephropathy: A worldwide problem. Kidney Int. 2008;74:158–169. doi: 10.1038/ki.2008.129. PubMed DOI

Cosyns J.P., Goebbels R.M., Liberton V., Schmeiser H.H., Bieler C.A., Bernard A.M. Chinese herbs nephropathy-associated slimming regimen induces tumours in the forestomach but no interstitial nephropathy in rats. Arch. Toxicol. 1998;72:738–743. doi: 10.1007/s002040050568. PubMed DOI

Cosyns J.P., Jadoul M., Squifflet J.P., Wese F.X., van Ypersele de Strihou C. Urothelial lesions in Chinese herb nephropathy. Am. J. Kidney Dis. 1999;33:1011–1017. doi: 10.1016/S0272-6386(99)70136-8. PubMed DOI

Jin K., Su K.K., Li T., Zhu X.Q., Wang Q., Ge R.S., Pan Z.F., Wu B.W., Ge L.J., Zhang Y.H., et al. Hepatic Premalignant Alterations Triggered by Human Nephrotoxin Aristolochic Acid I in Canines. Cancer Prev. Res. (Phila) 2016;9:324–334. doi: 10.1158/1940-6207.CAPR-15-0339. PubMed DOI

Li T., Jin K., Zhu D.Y., Li L., Mao Z.R., Wu B.W., Wang Y.F., Pan Z.F., Li L.J., Xiang C.S., et al. Premalignant alteration assessment in liver-like tissue derived from embryonic stem cells by aristolochic acid I exposure. Oncotarget. 2016;7:78872–78882. doi: 10.18632/oncotarget.12424. PubMed DOI PMC

Jadot I., Declèves A.E., Nortier J., Caron N. An integrated view of Aristolochic acid nephropathy: Update of the literature. Int. J. Mol. Sci. 2017;18:297. doi: 10.3390/ijms18020297. PubMed DOI PMC

Chan W., Pavlović N.M., Li W., Chan C.K., Liu J., Deng K., Wang Y., Milosavljević B., Kostić E.N. Quantitation of Aristolochic Acids in Corn, Wheat Grain, and Soil Samples Collected in Serbia: Identifying a Novel Exposure Pathway in the Etiology of Balkan Endemic Nephropathy. J. Agric. Food Chem. 2016;64:5928–5934. doi: 10.1021/acs.jafc.6b02203. PubMed DOI

Pfau W., Schmeiser H.H., Wiessler M. Aristolochic acid binds covalently to the exocyclic amino group of purine nucleotides in DNA. Carcinogenesis. 1990;11:313–319. doi: 10.1093/carcin/11.2.313. PubMed DOI

Pfau W., Schmeiser H.H., Wiessler M. 32P-postlabelling analysis of the DNA adducts formed by aristolochic acid I and II. Carcinogenesis. 1990;11:1627–1633. doi: 10.1093/carcin/11.9.1627. PubMed DOI

Schmeiser H.H., Bieler C.A., Wiessler M., van Ypersele de Strihou C., Cosyns J.P. Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy. Cancer Res. 1996;56:2025–2028. PubMed

Schmeiser H.H., Frei E., Wiessler M., Stiborová M. Comparison of DNA adduct formation by aristolochic acids in various in vitro activation systems by 32P-post-labelling: Evidence for reductive activation by peroxidases. Carcinogenesis. 1997;18:1055–1062. doi: 10.1093/carcin/18.5.1055. PubMed DOI

Stiborová M., Fernando R.C., Schmeiser H.H., Frei E., Pfau W., Wiessler M. Characterization of DNA adducts formed by aristolochic acids in the target organ (forestomach) of rats by 32P-postlabelling analysis using different chromatographic procedures. Carcinogenesis. 1994;15:1187–1192. doi: 10.1093/carcin/15.6.1187. PubMed DOI

Stiborová M., Mareš J., Frei E., Arlt V.M., Martínek V., Schmeiser H.H. The human carcinogen aristolochic acid I is activated to form DNA adducts by human NAD(P)H:quinone oxidoreductase without the contribution of acetyltransferases or sulfotransferases. Environ. Mol. Mutagen. 2011;52:448–459. doi: 10.1002/em.20642. PubMed DOI

Lord G.M., Cook T., Arlt V.M., Schmeiser H.H., Williams G., Pusey C.D. Urothelial malignant disease and Chinese herbal nephropathy. Lancet. 2001;358:1515–1516. doi: 10.1016/S0140-6736(01)06576-X. PubMed DOI

Lord G.M., Hollstein M., Arlt V.M., Roufosse C., Pusey C.D., Cook T., Schmeiser H.H. DNA adducts and p53 mutations in a patient with aristolochic acid-associated nephropathy. Am. J. Kidney Dis. 2004;43:e11–e17. doi: 10.1053/j.ajkd.2003.11.024. PubMed DOI

Arlt V.M., Stiborova M., vom Brocke J., Simoes M.L., Lord G.M., Nortier J.L., Hollstein M., Phillips D.H., Schmeiser H.H. Aristolochic acid mutagenesis: Molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer. Carcinogenesis. 2007;28:2253–2261. doi: 10.1093/carcin/bgm082. PubMed DOI

Aydin S., Dekairelle A.F., Ambroise J., Durant J.F., Heusterspreute M., Guiot Y., Cosyns J.P., Gala J.L. Unambiguous detection of multiple TP53 gene mutations in AAN-associated urothelial cancer in Belgium using laser capture microdissection. PLoS ONE. 2014;9:e106301. doi: 10.1371/journal.pone.0106301. PubMed DOI PMC

Aydin S., Ambroise J., Cosyns J.P., Gala J.L. TP53 mutations in p53-negative dysplastic urothelial cells from Belgian AAN patients: New evidence for aristolochic acid-induced molecular pathogenesis and carcinogenesis. Mutat. Res. 2017;818:17–26. doi: 10.1016/j.mrgentox.2017.03.003. PubMed DOI

Schmeiser H.H., Nortier J.L., Singh R., Gamboa da Costa G., Sennesael J., Cassuto-Viguier E., Ambrosetti D., Rorive S., Pozdzik A., Phillips D.H., 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;135:562–567. doi: 10.1002/ijc.28681. PubMed DOI

Schmeiser H.H., Janssen J.W., Lyons J., Scherf H.R., Pfau W., Buchmann A., Bartram C.R., Wiessler M. Aristolochic acid activates ras genes in rat tumors at deoxyadenosine residue. Cancer Res. 1990;50:5464–5469. PubMed

Schmeiser H.H., Scherf H.R., Wiessler M. Activating mutations at codon 61 of the c-Ha-ras gene in thin-tissue sections of tumors induced by aristolochic acid in rats and mice. Cancer Lett. 1991;59:139–143. doi: 10.1016/0304-3835(91)90178-K. PubMed DOI

Wang Y., Meng F., Arlt V.M., Mei N., Chen T., Parsons B.L. Aristolochic acid-induced carcinogenesis examined by ACB-PCR quantification of H-Ras and K-Ras mutant fraction. Mutagenesis. 2011;26:619–628. doi: 10.1093/mutage/ger023. PubMed DOI

Wang Y., Arlt V.M., Roufosse C.A., McKim K.L., Myers M.B., Phillips D.H., Parsons B.L. ACB-PCR measurement of H-ras codon 61 CAA→CTA mutation provides an early indication of aristolochic acid I carcinogenic effect in tumor target tissues. Environ. Mol. Mutagen. 2012;53:495–504. doi: 10.1002/em.21710. PubMed DOI

Broschard T.H., Wiessler M., von der Lieth C.W., Schmeiser H.H. Translesional synthesis on DNA templates containing site-specifically placed deoxyadenosine and deoxyguanosine adducts formed by the plant carcinogen aristolochic acid. Carcinogenesis. 1994;15:2331–2340. doi: 10.1093/carcin/15.10.2331. PubMed DOI

Moriya M., Slade N., Brdar B., Medverec Z., Tomic K., Jelakovic B., Wu L., Truong S., Fernandes A., Grollman A.P. TP53 Mutational signature for aristolochic acid: An environmental carcinogen. Int. J. Cancer. 2011;129:1532–1536. doi: 10.1002/ijc.26077. PubMed DOI

Olivier M., Hollstein M., Schmeiser H.H., Straif K., Wild C.P. Upper urinary tract urothelial cancer: Where it is A:T. Nat. Rev. Cancer. 2012;12:503–504. doi: 10.1038/nrc3311. PubMed DOI

Arlt V.M., Pfohl-Leszkowicz A., Cosyns J., Schmeiser H.H. Analyses of DNA adducts formed by ochratoxin A and aristolochic acid in patients with Chinese herbs nephropathy. Mutat. Res. 2001;494:143–150. doi: 10.1016/S1383-5718(01)00188-7. PubMed DOI

Bieler C.A., Stiborová M., Wiessler M., Cosyns J.-P., van Ypersele de Strihou C., Schmeiser H.H. 32P-postlabelling analysis of DNA adducts formed by aristolochic acid in tissues from patients with Chinese herbs nephropathy. Carcinogenesis. 1997;18:1063–1067. doi: 10.1093/carcin/18.5.1063. PubMed DOI

Arlt V.M., Ferluga D., Stiborova M., Pfohl-Leszkowicz A., Vukelic M., Ceovic S., Schmeiser H.H., Cosyns J.P. Is aristolochic acid a risk factor for Balkan endemic nephropathy-associated urothelial cancer? Int. J. Cancer. 2002;101:500–502. doi: 10.1002/ijc.10602. PubMed DOI

Grollman A.P., Shibutani S., Moriya M., Miller F., Wu L., Moll U., Suzuki N., Fernandes A., Rosenquist T., Medverec Z., et al. Aristolochic acid and the etiology of endemic Balkan nephropathy. Proc. Natl. Acad. Sci. USA. 2007;104:12129–12134. doi: 10.1073/pnas.0701248104. PubMed DOI PMC

Jelaković B., Karanović S., Vuković-Lela I., Miller F., Edwards K.L., Nikolić J., Tomić K., Slade N., Brdar B., Turesky R.J., 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. PubMed DOI PMC

Yun B.H., Rosenquist T.A., Sidorenko V., Iden C.R., Chen C.H., Pu Y.S., Bonala R., Johnson F., Dickman K.G., Grollman A.P., et al. Biomonitoring of aristolactam-DNA adducts in human tissues using ultra-performance liquid chromatography/ion-trap mass spectrometry. Chem. Res. Toxicol. 2012;25:1119–1131. doi: 10.1021/tx3000889. PubMed DOI PMC

Yun B.H., Rosenquist T.A., Nikolić J., Dragičević D., Tomić K., Jelaković B., Dickman K.G., Grollman A.P., Turesky R.J. Human formalin-fixed paraffin-embedded tissues: An untapped specimen for biomonitoring of carcinogen DNA adducts by mass spectrometry. Anal. Chem. 2013;85:4251–4258. doi: 10.1021/ac400612x. PubMed DOI PMC

Yun B.H., Sidorenko V.S., Rosenquist T.A., Dickman K.G., Grollman A.P., Turesky R.J. New approaches for biomonitoring exposure to the human carcinogen aristolochic acid. Toxicol. Res. (Camb) 2015;4:763–776. doi: 10.1039/C5TX00052A. PubMed DOI PMC

Schmeiser H.H., Stiborova M., Arlt V.M. 32P-postlabeling analysis of DNA adducts. Methods Mol. Biol. 2013;1044:389–401. doi: 10.1007/978-1-62703-529-3_21. PubMed DOI

Scelo G., Riazalhosseini Y., Greger L., Letourneau L., Gonzàlez-Porta M., Wozniak M.B., Bourgey M., Harnden P., Egevad L., Jackson S.M., et al. Variation in genomic landscape of clear cell renal cell carcinoma across Europe. Nat. Commun. 2014;5:5135. doi: 10.1038/ncomms6135. PubMed DOI

Turesky R.J., Yun B.H., Brennan P., Mates D., Jinga V., Harnden P., Banks R.E., Blanche H., Bihoreau M.T., Chopard P., et al. Aristolochic acid exposure in Romania and implications for renal cell carcinoma. Br. J. Cancer. 2016;114:76–80. doi: 10.1038/bjc.2015.402. PubMed DOI PMC

Chen C.H., Dickman K.G., Moriya M., Zavadil J., Sidorenko V.S., Edwards K.L., Gnatenko D.V., Wu L., Turesky R.J., Wu X.R., et al. Aristolochic acid-associated urothelial cancer in Taiwan. Proc. Natl. Acad. Sci. USA. 2012;109:8241–8246. doi: 10.1073/pnas.1119920109. PubMed DOI PMC

Chen C.H., Dickman K.G., Huang C.Y., Shun C.T., Tai H.C., Huang K.H., Wang S.M., Lee Y.J., Grollman A.P., Pu Y.S. Recurrence pattern and TP53 mutation in upper urinary tract urothelial carcinoma. Oncotarget. 2016;7:45225–45236. doi: 10.18632/oncotarget.9904. PubMed DOI PMC

Hoang M.L., Chen C.H., Sidorenko V.S., He J., Dickman K.G., Yun B.H., Moriya M., Niknafs N., Douville C., Karchin R., et al. Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Sci. Transl. Med. 2013;5:197ra102. doi: 10.1126/scitranslmed.3006200. PubMed DOI PMC

Poon S.L., Pang S.T., McPherson J.R., Yu W., Huang K.K., Guan P., Weng W.H., Siew E.Y., Liu Y., Heng H.L., et al. Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci. Transl. Med. 2013;5:197ra101. doi: 10.1126/scitranslmed.3006086. PubMed DOI

Sidorenko V.S., Yeo J.E., Bonala R.R., Johnson F., Schärer O.D., Grollman A.P. Lack of recognition by global-genome nucleotide excision repair accounts for the high mutagenicity and persistence of aristolactam-DNA adducts. Nucleic Acids Res. 2012;40:2494–2505. doi: 10.1093/nar/gkr1095. PubMed DOI PMC

Nik-Zainal S., Kucab J.E., Morganella S., Glodzik D., Alexandrov L.B., Arlt V.M., Weninger A., Hollstein M., Stratton M.R., Phillips D.H. The genome as a record of environmental exposure. Mutagenesis. 2015;30:763–770. doi: 10.1093/mutage/gev073. PubMed DOI PMC

National Toxicology Program . Aristolochic Acids 12th Report on Carcinogens. National Toxicology Program; Public Health Service, US Department of Health and Human Services; Research Triangle Park, NC, USA: 2009. pp. 45–49.

Gillerot G., Jadoul M., Arlt V.M., van Ypersele de Strihou C., Schmeiser H.H., But P.P., Bieler C.A., Cosyns J.P. Aristolochic acid nephropathy in a Chinese patient: Time to abandon the term “Chinese herbs nephropathy”? Am. J. Kidney Dis. 2001;38:E26. doi: 10.1053/ajkd.2001.28624. PubMed DOI

Nortier J.L., Schmeiser H.H., Muniz Martinez M.C., Arlt V.M., Vervaet C., Garbar C.H., Daelemans P., Vanherweghem J.L. Invasive urothelial carcinoma after exposure to Chinese herbal medicine containing aristolochic acid may occur without severe renal failure. Nephrol. Dial. Transplant. 2003;18:426–428. doi: 10.1093/ndt/18.2.426. PubMed DOI

Lo S.H., Wong K.S., Arlt V.M., Phillips D.H., Lai C.K., Poon W.T., Chan C.K., Mo K.L., Chan K.W., Chan A. Detection of Herba Aristolochia Mollissemae in a patient with unexplained nephropathy. Am. J. Kidney Dis. 2005;45:407–410. doi: 10.1053/j.ajkd.2004.09.019. PubMed DOI

Yun B.H., Yao L., Jelaković B., Nikolić J., Dickman K.G., Grollman A.P., Rosenquist T.A., Turesky R.J. Formalin-fixed paraffin-embedded tissue as a source for quantitation of carcinogen DNA adducts: Aristolochic acid as a prototype carcinogen. Carcinogenesis. 2014;35:2055–2061. doi: 10.1093/carcin/bgu101. PubMed DOI PMC

Roumeguère T., Broeders N., Jayaswal A., Rorive S., Quackels T., Pozdzik A., Arlt V.M., Schmeiser H.H., Nortier J.L. Bacillus Calmette-Guerin therapy in non-muscle-invasive bladder carcinoma after renal transplantation for end-stage aristolochic acid nephropathy. Transpl. Int. 2015;28:199–205. doi: 10.1111/tri.12484. PubMed DOI

Bamias G., Boletis J. Balkan nephropathy: Evolution of our knowledge. Am. J. Kidney Dis. 2008;52:606–616. doi: 10.1053/j.ajkd.2008.05.024. PubMed DOI PMC

Tatu C.A., Orem W.H., Finkelman R.B., Feder G.L. The etiology of Balkan endemic nephropathy: Still more questions than answers. Environ. Health Perspect. 1998;106:689–700. PubMed PMC

Krumbiegel G., Hallensleben J., Mennicke W.H., Rittmann N. Studies on the metabolism of aristolochic acids I and II. Xenobiotica. 1987;17:981–991. doi: 10.3109/00498258709044197. PubMed DOI

Chan W., Cu L., Xu G., Cai Z. 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. PubMed DOI

Chan W., Luo H.B., Zheng Y., Cheng Y.K., Cai Z. Investigation of the metabolism and reductive activation of carcinogenic aristolochic acid in rats. Drug Metab. Dispos. 2007;35:866–874. doi: 10.1124/dmd.106.013979. PubMed DOI

Schmeiser H.H., Pool B.L., Wiessler M. Identification and mutagenicity of metabolites of aristolochic acid formed by rat liver. Carcinogenesis. 1986;7:759–763. doi: 10.1093/carcin/7.1.59. PubMed DOI

Shibutani S., Bonala R.R., Rosenquist T., Rieger R., Suzuki N., Johnson F., Miller F., Grollman A.P. Detoxification of aristolochic acid I by O-demethylation: Less nephrotoxicity and genotoxicity of aristolochic acid Ia in rodents. Int. J. Cancer. 2010;127:1021–1027. doi: 10.1002/ijc.25141. PubMed DOI PMC

Dong H., Suzuki N., Torres M.C., Bonala R.R., Johnson F., Grollman A.P., Shibutani S. Quantitative determination of aristolochic acid-derived DNA adducts in rats using 32P-postlabeling/polyacrylamide gel electrophoresis analysis. Drug Metab. Dispos. 2006;34:1122–1127. doi: 10.1124/dmd.105.008706. PubMed DOI

Stiborová M., Levová K., Bárta F., Shi Z., Frei E., Schmeiser H.H., Nebert D.W., Phillips D.H., Arlt V.M. Bioactivation versus detoxication of the urothelial carcinogen aristolochic acid I by human cytochrome P450 1A1 and 1A2. Toxicol. Sci. 2012;125:345–358. doi: 10.1093/toxsci/kfr306. PubMed DOI PMC

Sistkova J., Hudecek J., Hodek P., Frei E., Schmeiser H.H., Stiborova M. Human cytochromes P450 1A1 and 1A2 participate in detoxication of carcinogenic aristolochic acid. Neuro Endocrinol. Lett. 2008;29:733–737. PubMed

Rosenquist T.A., Einolf H.J., Dickman K.G., Wang L., Smith A., Grollman A.P. Cytochrome P450 1A2 detoxicates aristolochic acid in the mouse. Drug Metab. Dispos. 2010;38:761–768. doi: 10.1124/dmd.110.032201. PubMed DOI PMC

Levová K., Mizerovská M., Kotrbová V., Šulc M., Henderson C.J., Wolf C.R., Philips D.H., Frei E., Schmeiser H.H., Mareš J., et al. Role of cytochromes P450 1A1/2 in detoxication and activation of carcinogenic aristolochic acid I: Studies with the hepatic NADPH:cytochrome P450 reductase null (HRN) mouse model. Toxicol. Sci. 2011;121:43–56. doi: 10.1093/toxsci/kfr050. PubMed DOI

Stiborová M., Bárta F., Levová K., Hodek P., Schmeiser H.H., Arlt V.M., Martínek V. A mechanism of O-demethylation of aristolochic acid I by cytochromes P450 and their contributions to this reaction in human and rat livers: Experimental and theoretical approaches. Int. J. Mol. Sci. 2015;16:27561–27575. doi: 10.3390/ijms161126047. PubMed DOI PMC

Arlt V.M., Levova K., Barta F., Shi Z., Evans J.D., Frei E., Schmeiser H.H., Nebert D.W., Phillips D.H., Stiborova M. Role of P450 1A1 and P450 1A2 in bioactivation versus detoxication of the renal carcinogen aristolochic acid I: Studies in Cyp1a1(−/−), Cyp1a2(−/−), and Cyp1a1/1a2(−/−) mice. Chem. Res. Toxicol. 2011;24:1710–1719. doi: 10.1021/tx200259y. PubMed DOI

Dračínská H., Bárta F., Levová K., Hudecová A., Moserová M., Schmeiser H.H., Kopka K., Frei E., Arlt V.M., Stiborová M. Induction of cytochromes P450 1A1 and 1A2 suppresses formation of DNA adducts by carcinogenic aristolochic acid I in rats in vivo. Toxicology. 2016;344:7–8. doi: 10.1016/j.tox.2016.01.011. PubMed DOI PMC

Xue X., Xiao Y., Zhu H., Wang H., Liu Y., Xie T., Ren J. Induction of P450 1A by 3-methylcholanthrene protects mice from aristolochic acid-I-induced acute renal injury. Nephrol. Dial. Transplant. 2008;23:3074–3081. doi: 10.1093/ndt/gfn262. PubMed DOI

Xiao Y., Ge M., Xue X., Wang H., Wu X., Li L., Liu L., Qi X., Zhang Y., Li Y., et al. Detoxication role of hepatic cytochrome P450s in the kidney toxicity induced by aristolochic acid. Kidney Int. 2008;73:1231–1239. doi: 10.1038/ki.2008.103. PubMed DOI

Martínek V., Bárta F., Hodek P., Frei E., Schmeiser H.H., Arlt V.M., Stiborová M. Comparison of the oxidation of carcinogenic aristolochic acid I and II by microsomal cytochromes P450 in vitro: Experimental and theoretical approaches. Monatshefte Chem. 2017 PubMed PMC

Stiborova M., Barta F., Dracinska H., Hudecova A., Hodek P., Balogova M., Mraz J., Duskova S., Schmeiser H.H., Arlt V.M. Treatment with a mixture of aristolochic acid I and II influences their genotoxicity and expression of biotransformation enzymes in rats in vivo. Toxicol. Lett. 2016;256:S96. doi: 10.1016/j.toxlet.2016.06.1416. DOI

Schmeiser H., Schoepe K.B., Wiessler M. DNA adduct formation of aristolochic acid I and II in vitro and in vivo. Carcinogenesis. 1988;9:297–303. doi: 10.1093/carcin/9.2.297. PubMed DOI

Shibutani S., Dong H., Suzuki N., Ueda S., Miller F., Grollman A.P. Selective toxicity of aristolochic acids I and II. Drug Metab. Dispos. 2007;35:1217–1222. doi: 10.1124/dmd.107.014688. PubMed DOI

Arlt V.M., Meinl W., Florian S., Nagy E., Barta F., Thomann M., Mrizova I., Krais A.M., Liu M., Richards M., et al. Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone. Arch. Toxicol. 2017;91:1957–1975. doi: 10.1007/s00204-016-1808-6. PubMed DOI PMC

Stiborová M., Frei E., Wiessler M., Schmeiser H.H. Human enzymes involved in the metabolic activation of carcinogenic aristolochic acids: Evidence for reductive activation by cytochromes P450 1A1 and 1A2. Chem. Res. Toxicol. 2001;14:1128–1137. doi: 10.1021/tx010059z. PubMed DOI

Stiborová M., Hájek M., Frei E., Schmeiser H.H. Carcinogenic and nephrotoxic alkaloids aristolochic acids upon activation by NADPH:cytochrome P450 reductase form adducts found in DNA of patients with Chinese herbs nephropathy. Gen. Physiol. Biophys. 2001;20:375–392. PubMed

Stiborová M., Frei E., Breuer A., Wiessler M., Schmeiser H.H. Evidence for reductive activation of carcinogenic aristolochic acids by prostaglandin H synthase—32P-postlabeling analysis of DNA adduct formation. Mutat. Res. 2001;493:149–160. doi: 10.1016/S1383-5718(01)00171-1. PubMed DOI

Stiborová M., Frei E., Sopko B., Wiessler M., Schmeiser H.H. Carcinogenic aristolochic acids upon activation by DT-diaphorase form adducts found in DNA of patients with Chinese herbs nephropathy. Carcinogenesis. 2002;23:617–625. doi: 10.1093/carcin/23.4.617. PubMed DOI

Martínek V., Kubickova B., Arlt V.M., Frei E., Schmeiser H.H., Hudeček J., Stiborova M. Comparison of activation of aristolochic acid I and II with NADPH:quinone oxidoreductase, sulphotransferases and N-acetyltransferases. Neuro Endocrinol. Lett. 2011;32(Suppl. S1):S57–S70. PubMed

Stiborová M., Hudeček J., Frei E., Schmeiser H.H. Contribution of biotransformation enzymes to the development of renal injury and urothelial cancer caused by aristolochic acid: Urgent questions, difficult answers. Interdiscip. Toxicol. 2008;1:8–12. doi: 10.2478/v10102-010-0023-1. PubMed DOI PMC

Stiborová M., Frei E., Sopko B., Sopková K., Marková V., Laňková M., Kumstýřová T., Wiessler M., Schmeiser H.H. Human cytosolic enzymes involved in the metabolic activation of carcinogenic aristolochic acid: Evidence for reductive activation by human NAD(P)H:quinone oxidoreductase. Carcinogenesis. 2003;24:1695–1703. doi: 10.1093/carcin/bgg119. PubMed DOI

Chen M., Gong L., Qi X., Xing G., Luan Y., Wu Y., Xiao Y., Yao J., Li Y., Xue X., et al. Inhibition of renal NQO1 activity by dicoumarol suppresses nitroreduction of aristolochic acid I and attenuates its nephrotoxicity. Toxicol. Sci. 2011;122:288–296. doi: 10.1093/toxsci/kfr138. PubMed DOI

Stiborová M., Frei E., Arlt V.M., Schmeiser H.H. Knock-out and humanized mice as suitable tools to identify enzymes metabolizing the human carcinogen aristolochic acid. Xenobiotica. 2014;44:135–145. doi: 10.3109/00498254.2013.848310. PubMed DOI

Stiborová M., Frei E., Schmeiser H.H., Arlt V.M., Martínek V. Mechanisms of enzyme-catalyzed reduction of two carcinogenic nitro-aromatics, 3-nitrobenzanthrone and aristolochic acid I: Experimental and theoretical approaches. Int. J. Mol. Sci. 2014;15:10271–10295. doi: 10.3390/ijms150610271. PubMed DOI PMC

Stiborová M., Levová K., Bárta F., Šulc M., Frei E., Arlt V.M., Schmeiser H.H. The influence of dicoumarol on the bioactivation of the carcinogen aristolochic acid I in rats. Mutagenesis. 2014;29:189–200. doi: 10.1093/mutage/geu004. PubMed DOI

Sidorenko V.S., Attaluri S., Zaitseva I., Iden C.R., Dickman K.G., Johnson F., Grollman A.P. Bioactivation of the human carcinogen aristolochic acid. Carcinogenesis. 2014;35:1814–1822. doi: 10.1093/carcin/bgu095. PubMed DOI PMC

Hashimoto K., Zaitseva I.N., Bonala R., Attaluri S., Ozga K., Iden C.R., Johnson F., Moriya M., Grollman A.P., Sidorenko V.S. Sulfotransferase-1A1-dependent bioactivation of aristolochic acid I and N-hydroxyaristolactam I in human cells. Carcinogenesis. 2016;37:647–655. doi: 10.1093/carcin/bgw045. PubMed DOI PMC

Meinl W., Pabel U., Osterloh-Quiroz M., Hengstler J.G., Glatt H. Human sulphotransferases are involved in the activation of aristolochic acids and are expressed in renal target tissue. Int. J. Cancer. 2006;118:1090–1097. doi: 10.1002/ijc.21480. PubMed DOI

Stiborová M., Frei E., Hodek P., Wiessler M., Schmeiser H.H. Human hepatic and renal microsomes, cytochromes P450 1A1/2, NADPH:CYP reductase and prostaglandin H synthase mediate the formation of aristolochic acid DNA-adducts found in patients with urothelial cancer. Int. J. Cancer. 2005;113:189–197. doi: 10.1002/ijc.20564. PubMed DOI

Stiborová M., Sopko B., Hodek P., Frei E., Schmeiser H.H., Hudeček J. The binding of aristolochic acid I to the active site of human cytochromes P450 1A1 and 1A2 explains their potential to reductively activate this human carcinogen. Cancer Lett. 2005;229:193–204. doi: 10.1016/j.canlet.2005.06.038. PubMed DOI

Milichovský J., Bárta F., Schmeiser H.H., Arlt V.M., Frei E., Stiborová M., Martínek V. Active site mutations as a suitable tool contributing to explain a mechanism of aristolochic acid I nitroreduction by cytochromes P450 1A1, 1A2, and 1B1. Int. J. Mol. Sci. 2016;7:213. doi: 10.3390/ijms17020213. PubMed DOI PMC

Jerabek P., Martinek V., Stiborova M. Theoretical investigation of differences in nitroreduction of aristolochic acid I by cytochromes P450 1A1, 1A2 and 1B1. Neuro Endocrinol. Lett. 2012;33(Suppl. S3):25–32. PubMed

Guengerich F.P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem. Res. Toxicol. 2001;14:611–650. doi: 10.1021/tx0002583. PubMed DOI

Guengerich F.P. Cytochrome P450 and chemical toxicology. Chem. Res. Toxicol. 2008;21:70–83. doi: 10.1021/tx700079z. PubMed DOI

Rendic S., DiCarlo F.J. Human cytochrome P450 enzymes: A status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab. Rev. 1997;29:413–480. doi: 10.3109/03602539709037591. PubMed DOI

Atanasova S.Y., von Ahsen N., Toncheva D.I., Dimitrov T.G., Oellerich M., Amstrong V.M. Genetic polymorphism of cytochrome P450 among patients with Balkan endemic nephropathy (BEN) Clin. Biochem. 2005;38:223–228. doi: 10.1016/j.clinbiochem.2004.12.002. PubMed DOI

Ross D., Kepa J.K., Winski S.L., Beall H.D., Anwar A., Siegel D. NAD(P)H:quinone oxidoreductase 1 (NQO1): Chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem. Biol. Interact. 2000;129:77–97. doi: 10.1016/S0009-2797(00)00199-X. PubMed DOI

Ross D. Quinone reductases multitasking in the metabolic world. Drug Metab. Rev. 2004;36:639–654. doi: 10.1081/DMR-200033465. PubMed DOI

Bárta F., Levová K., Frei E., Schmeiser H.H., Arlt V.M., Stiborová M. The effect of aristolochic acid I on NAD(P)H:quinone oxidoreductase expression in mice and rats—A comparative study. Mutat. Res. 2014;768:1–7. doi: 10.1016/j.mrgentox.2014.01.012. PubMed DOI

Toncheva D., Dimitrov T., Stojanova S. Etiology of Balkan endemic nephropathy: A multifactorial disease? Eur. J. Epidemiol. 1998;14:389–394. doi: 10.1023/A:1007445120729. PubMed DOI

Toncheva D.I., von Ahsen N., Atanasova S.Y., Dimitrov T.G., Armstrong V.M., Oellerich M. Identification of NQO1 and GSTs genotype frequencies in Bulgarian patients with Balkan endemic nephropathy. J. Nephrol. 2004;17:384–389. PubMed

He P., Court R.H., Greenblatt D.J., Von Moltke L.L. Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin. Pharmacol. Ther. 2005;77:373–387. doi: 10.1016/j.clpt.2004.11.112. PubMed DOI

Stefanović V., Toncheva D., Atanasova S., Polenaković M. Etiology of Balkan endemic nephropathy and associated urothelial cancer. Am. J. Nephrol. 2006;26:1–11. doi: 10.1159/000090705. PubMed DOI

Toncheva D. Genetic studies in BEN and associated urothelial cancers. Coll. Antropol. 2006;30(Suppl. S1):34.

Chen B., Bai Y., Sun M., Ni X., Yang Y., Yang Y., Zheng S., Xu F., Dai S. Glutathione S-transferases T1 null genotype is associated with susceptibility to aristolochic acid nephropathy. Int. Urol. Nephrol. 2012;44:301–307. doi: 10.1007/s11255-011-0082-z. PubMed DOI

Wang B., Wang J., Huang S.Q., Su H.H., Zhou S.F. Genetic polymorphism of the human cytochrome P450 2C9 gene and its clinical significance. Curr. Drug Metab. 2009;10:781–834. doi: 10.2174/138920009789895480. PubMed DOI

Reljic Z., Zlatovic M., Savic-Radojevic A., Pekmezovic T., Djukanovic L., Matic M., Pljesa-Ercegovac M., Mimic-Oka J., Opsenica D., Simic T. Is increased susceptibility to Balkan endemic nephropathy in carriers of common GSTA1 (*A/*B) polymorphism linked with the catalytic role of GSTA1 in ochratoxin a biotransformation? Serbian case control study and in silico analysis. Toxins. 2014;6:2348–2362. doi: 10.3390/toxins6082348. PubMed DOI PMC

The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro