{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:59:58Z","timestamp":1791824398816,"version":"4.3.4"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005950","name":"Hong Kong University of Science and Technology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005950","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Aristolochic acids (AAs), derived from\n                    <jats:italic>Aristolochia<\/jats:italic>\n                    herbs, are well-known nephrotoxins, and emerging evidence suggests their potential role in the development of liver cancers. However, the specific organs most affected by AAs, particularly in relation to liver cancer, remain unclear. Considering the known sex differences in enzyme activities, we hypothesized that variations in AA metabolism may contribute to the kidney and liver toxicity associated with these compounds. Our analysis of DNA adducts in the kidneys and livers of mice treated with aristolochic acid I (AA-I) revealed that male mice exhibited over 2.5 times higher levels of DNA adducts in their kidney DNA compared to female mice. Conversely, female mice showed 1.5 times higher adduct levels in their liver DNA than their male counterparts. These findings indicate that AA exposure presents a sex-specific disease risk, with males being at greater risk for kidney disease and females for liver disease. Additionally, we observed similar concentration patterns of the metabolite aristolactam I (AL-I) and the activity of NQO1 enzymes in the respective organs. Further in vitro studies, involving the incubation of AA-I with liver and kidney homogenates, demonstrated significant differences in AL-I concentrations, mirroring the trends observed in the AA-DNA adduct and AL-I analyses of AA-I-exposed mice. Collectively, these results underscore the importance of sex differences in the enzymatic activity responsible for the metabolic activation of AAs, which is critical for understanding the differential nephrotoxic and hepatotoxic effects associated with these compounds.\n                  <\/jats:p>","DOI":"10.1007\/s00204-025-04297-5","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:32:27Z","timestamp":1768955547000},"page":"1575-1587","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sex-specific toxicity targets of aristolochic acids: nephrotoxicity in males, hepatotoxicity in females"],"prefix":"10.1007","volume":"100","author":[{"given":"Hong-Ching","family":"Kwok","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikola M.","family":"Pavlovi\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongwei","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8479-3172","authenticated-orcid":false,"given":"Wan","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"4297_CR1","doi-asserted-by":"publisher","first-page":"100447","DOI":"10.1016\/j.hermed.2021.100447","volume":"28","author":"LP Ang","year":"2021","unstructured":"Ang LP, Ng PW, Lean YL, Kotra V, Kifli N, Goh HP, Lee KS, Sarker MMR, Al-Worafi YM, Ming LC (2021) Herbal products containing aristolochic acids: a call to revisit the context of safety. J Herb Med 28:100447. https:\/\/doi.org\/10.1016\/j.hermed.2021.100447","journal-title":"J Herb Med"},{"key":"4297_CR18","unstructured":"Anttila A, Bhat RV, Bond JA, Borghoff SJ, Bosch FX, Carlson GP, Castegnaro M, Cruzan G, Gelderblom WCA, Hass U, Henry SH, Herbert RA, Jackson M, Jiang T, Kinghorn AD, Knasm\u00fcller S, Levy L, McGregor D, Miller JD, Mori H, Olin SS, Park DL, Pitt JI, Riley RT, Schmeiser HH, Siemiatycki J, Vanherweghem JL, Wild CP, Yoshizawa T (2002) IARC monographs on the evaluation of carcinogenic risks to humans: some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC monographs on the evaluation of carcinogenic risks to humans. 82:i\u2013551"},{"key":"4297_CR31","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1093\/mutage\/17.4.265","volume":"17","author":"VM Arlt","year":"2002","unstructured":"Arlt VM, Stiborova M, Schmeiser HH (2002) Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis 17:265\u2013277. https:\/\/doi.org\/10.1093\/mutage\/17.4.265","journal-title":"Mutagenesis"},{"key":"4297_CR37","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1021\/acs.chemrestox.0c00004","volume":"33","author":"CK Au","year":"2020","unstructured":"Au CK, Chan CK, Tung KK, Zhang J, Chan W (2020) Quantitation of DNA adducts of aristolochic acids in repair-deficient cells: a mechanistic study of the DNA repair mechanism. Chem Res Toxicol 33:1323\u20131327. https:\/\/doi.org\/10.1021\/acs.chemrestox.0c00004","journal-title":"Chem Res Toxicol"},{"key":"4297_CR41","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1021\/acs.chemrestox.2c00415","volume":"36","author":"CK Au","year":"2023","unstructured":"Au CK, Ham YH, Chan W (2023) Bioaccumulation and DNA adduct formation of aristolactam I: unmasking a toxicological mechanism in the pathophysiology of aristolochic acid nephropathy. Chem Res Toxicol 36:322\u2013329. https:\/\/doi.org\/10.1021\/acs.chemrestox.2c00415","journal-title":"Chem Res Toxicol"},{"key":"4297_CR42","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.1021\/acs.chemrestox.1c00175","volume":"34","author":"W Chan","year":"2021","unstructured":"Chan W, Ham YH (2021) Probing the hidden role of mitochondrial DNA damage and dysfunction in the etiology of aristolochic acid nephropathy. Chem Res Toxicol 34:1903\u20131909. https:\/\/doi.org\/10.1021\/acs.chemrestox.1c00175","journal-title":"Chem Res Toxicol"},{"key":"4297_CR5","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.aca.2006.03.008","volume":"576","author":"W Chan","year":"2006","unstructured":"Chan W, Hui KM, Poon WT, Lee KC, Cai Z (2006) Differentiation of herbs linked to Chinese herb nephropathy from the liquid chromatographic determination of aristolochic acids. Anal Chim Acta 576:112\u2013116. https:\/\/doi.org\/10.1016\/j.aca.2006.03.008","journal-title":"Anal Chim Acta"},{"key":"4297_CR52","doi-asserted-by":"publisher","first-page":"S20","DOI":"10.1186\/1471-2105-7-S2-S20","volume":"7","author":"T Chen","year":"2006","unstructured":"Chen T, Guo L, Zhang L, Shi L, Fang H, Sun Y, Fuscoe JC, Mei N (2006) Gene expression profiles distinguish the carcinogenic effects of aristolochic acid in target (kidney) and non-target (liver) tissues in rats. BMC Bioinf 7:S20. https:\/\/doi.org\/10.1186\/1471-2105-7-S2-S20","journal-title":"BMC Bioinf"},{"key":"4297_CR6","doi-asserted-by":"publisher","unstructured":"Chen CH, Dickman KG, Moriya M, Zavadil J, Sidorenko VS, Edwards KL, Gnatenko DV, Wu L, Turesky RJ, Wu XR, Pu YS, Grollman AP (2012) Aristolochic acid-associated urothelial cancer in Taiwan. Proc Natl Acad Sci U S A 109: 8241\u20138246. https:\/\/doi.org\/10.1073\/pnas.1119920109","DOI":"10.1073\/pnas.1119920109"},{"key":"4297_CR12","doi-asserted-by":"publisher","first-page":"2252","DOI":"10.1016\/j.apsb.2021.11.011","volume":"12","author":"S Chen","year":"2020","unstructured":"Chen S, Dong Y, Qi X, Cao Q, Luo T, Bai Z, He H, Fan Z, Xu L, Xing G, Wang C, Jin Z, Li Z, Chen L, Zhong Y, Wang J, Ge J, Xiao X, Bian X, Wen W, Ren J, Wang H (2020) Aristolochic acids exposure was not the main cause of liver tumorigenesis in adulthood. Acta Pharm Sin B 12:2252\u20132267. https:\/\/doi.org\/10.1016\/j.apsb.2021.11.011","journal-title":"Acta Pharm Sin B"},{"key":"4297_CR15","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1080\/15563650600671712","volume":"44","author":"TP Cheung","year":"2006","unstructured":"Cheung TP, Xue C, Leung K, Chan K, Li CG (2006) Aristolochic acids detected in some raw Chinese medicinal herbs and manufactured herbal products\u2013A consequence of inappropriate nomenclature and imprecise labelling? Clin Toxicol 44:371\u2013378. https:\/\/doi.org\/10.1080\/15563650600671712","journal-title":"Clin Toxicol"},{"key":"4297_CR30","doi-asserted-by":"publisher","first-page":"33","DOI":"10.2165\/00002018-200326010-00004","volume":"26","author":"JP Cosyns","year":"2003","unstructured":"Cosyns JP (2003) Aristolochic acid and \u2018Chinese herbs nephropathy\u2019 a review of the evidence to date. Drug Saf 26:33\u201348. https:\/\/doi.org\/10.2165\/00002018-200326010-00004","journal-title":"Drug Saf"},{"key":"4297_CR4","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/ki.2008.129","volume":"74","author":"FD Debelle","year":"2008","unstructured":"Debelle FD, Vanherweghem JL, Nortier JL (2008) Aristolochic acid nephropathy: a worldwide problem. Kidney Int 74:158\u2013169. https:\/\/doi.org\/10.1038\/ki.2008.129","journal-title":"Kidney Int"},{"key":"4297_CR23","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1007\/s00345-022-04100-5","volume":"41","author":"KG Dickman","year":"2023","unstructured":"Dickman KG, Chen CH, Grollman AP, Pu YS (2023) Aristolochic acid-containing Chinese herbal medicine and upper urinary tract urothelial carcinoma in Taiwan: a narrative review. World J Urol 41:899\u2013907. https:\/\/doi.org\/10.1007\/s00345-022-04100-5","journal-title":"World J Urol"},{"key":"4297_CR13","doi-asserted-by":"publisher","first-page":"840961","DOI":"10.3389\/fgene.2022.840961","volume":"13","author":"ZE Fang","year":"2022","unstructured":"Fang ZE, Wang C, Niu M, Liu T, Ren L, Li Q, Li Z, Wei Z, Lin L, Mu W, Gao Y, Xiao X, Bai Z (2022) Integration of transcriptomic and metabolomic data to compare the hepatotoxicity of neonatal and adult mice exposed to aristolochic acid I. Front Genet 13:840961. https:\/\/doi.org\/10.3389\/fgene.2022.840961","journal-title":"Front Genet"},{"key":"4297_CR49","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1093\/carcin\/bgl219","volume":"124","author":"RC Fernando","year":"1993","unstructured":"Fernando RC, Schmeiser HH, Scherf HR, Wiessler M (1993) Formation and persistence of specific purine DNA adducts by 32P-postlabelling in target and non-target organs of rats treated with aristolochic acid I. IARC Sci Publ 124:167\u2013171. https:\/\/doi.org\/10.1093\/carcin\/bgl219","journal-title":"IARC Sci Publ"},{"key":"4297_CR19","doi-asserted-by":"publisher","first-page":"469","DOI":"10.7326\/0003-4819-158-6-201303190-0000","volume":"158","author":"MR G\u00f6kmen","year":"2013","unstructured":"G\u00f6kmen MR, Cosyns JP, Arlt VM, Stiborov\u00e1 M, Phillips DH, Schmeiser HH, Simmonds MSJ, Cook HT, Vanherweghem JL, Nortier JL, Lord GM (2013) The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review. Ann Intern Med 158:469\u2013477. https:\/\/doi.org\/10.7326\/0003-4819-158-6-201303190-0000","journal-title":"Ann Intern Med"},{"key":"4297_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/em.21756","volume":"54","author":"AP Grollman","year":"2013","unstructured":"Grollman AP (2013) Aristolochic acid nephropathy: harbinger of a global iatrogenic disease. Environ Mol Mutagen 54:1\u20137. https:\/\/doi.org\/10.1002\/em.21756","journal-title":"Environ Mol Mutagen"},{"key":"4297_CR44","doi-asserted-by":"publisher","first-page":"12129","DOI":"10.1073\/pnas.0701248104","volume":"104","author":"AP Grollman","year":"2007","unstructured":"Grollman AP, Shibutani S, Moriya M, Miller F, Wu L, Moll U, Suzuki N, Fernandes A, Rosenquist T, Medverec Z, Jakovina K, Brdar B, Slade N, Turesky RJ, Goodenough AK, Rieger R, Vukelic M, Jelakovi\u0107 B (2007) Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A 104:12129\u201312134. https:\/\/doi.org\/10.1073\/pnas.0701248104","journal-title":"Proc Natl Acad Sci U S A"},{"key":"4297_CR39","doi-asserted-by":"publisher","first-page":"11301","DOI":"10.1021\/acs.est.4c02848","volume":"58","author":"W Guo","year":"2024","unstructured":"Guo W, Kwok HC, Griffith SM, Nagl S, Milovanovic D, Pavlovic M, Yu JZ, Dedon PC, Chan W (2024) Combustion-derived pollutants linked with kidney disease in low-lying flood-affected areas in the Balkans. Environ Sci Technol 58:11301\u201311308. https:\/\/doi.org\/10.1021\/acs.est.4c02848","journal-title":"Environ Sci Technol"},{"key":"4297_CR3","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/s0378-8741(98)00123-8","volume":"64","author":"K Hashimoto","year":"1999","unstructured":"Hashimoto K, Higuchi M, Makino B, Sakakibara I, Kubo M, Komatsu Y, Maruno M, Okada M (1999) Quantitative analysis of aristolochic acids, toxic compounds, contained in some medicinal plants. J Ethnopharmacol 64:185\u2013189. https:\/\/doi.org\/10.1016\/s0378-8741(98)00123-8","journal-title":"J Ethnopharmacol"},{"key":"4297_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1749-8546-3-13","volume":"3","author":"SC Hsieh","year":"2008","unstructured":"Hsieh SC, Lin IH, Tseng WL, Lee CH, Wang JD (2008) Prescription profile of potentially aristolochic acid containing Chinese herbal products: an analysis of National health insurance data in Taiwan between 1997 and 2003. Chin Med 3:1\u20136. https:\/\/doi.org\/10.1186\/1749-8546-3-13","journal-title":"Chin Med"},{"key":"4297_CR21","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.tox.2004.01.026","volume":"198","author":"S Hu","year":"2004","unstructured":"Hu S, Zhang H, Chan K, Mei Q (2004) Studies on the toxicity of aristolochia manshuriensis (guanmuton). Toxicology 198:195\u2013201. https:\/\/doi.org\/10.1016\/j.tox.2004.01.026","journal-title":"Toxicology"},{"key":"4297_CR25","doi-asserted-by":"publisher","first-page":"297","DOI":"10.3390\/ijms18020297","volume":"18","author":"I Jadot","year":"2017","unstructured":"Jadot I, Decl\u00e8ves A, Nortier J, Caron N (2017) An integrated view of aristolochic acid nephropathy: update of the literature. Int J Mol Sci 18:297. https:\/\/doi.org\/10.3390\/ijms18020297","journal-title":"Int J Mol Sci"},{"key":"4297_CR2","doi-asserted-by":"publisher","first-page":"3057","DOI":"10.1081\/JLC-120025422","volume":"26","author":"J Jou","year":"2003","unstructured":"Jou J, Chen S, Wu T (2003) Facile reversed-phase HPLC resolution and quantitative determination of aristolochic acid and aristolactam analogues in traditional Chinese medicine. J Liq Chromatogr Rel Technol 26:3057\u20133068. https:\/\/doi.org\/10.1081\/JLC-120025422","journal-title":"J Liq Chromatogr Rel Technol"},{"key":"4297_CR51","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S1383-5718(01)00350-3","volume":"515","author":"A Kohara","year":"2002","unstructured":"Kohara A, Suzuki T, Honma M, Ohwada T, Hayashi M (2002) Mutagenicity of aristolochic acid in the lambda\/lacZ Transgenic mouse (Muta\u2122 Mouse). Mutat Res Genet Toxicol Environ Mutagen 515:63\u201372. https:\/\/doi.org\/10.1016\/S1383-5718(01)00350-3","journal-title":"Mutat Res Genet Toxicol Environ Mutagen"},{"key":"4297_CR43","doi-asserted-by":"crossref","unstructured":"Kwok HC, Tse HT, Ng KK, Wang S, Au CK, Cai Z, Chan W (2025) Absorptivity is an important determinant in the toxicity difference between aristolochic acid I and aristolochic acid II. J. Agric. Food Chem. 73:2551\u20132561","DOI":"10.1021\/acs.jafc.4c10765"},{"key":"4297_CR54","doi-asserted-by":"publisher","unstructured":"Ham YH, Chin ML, Pan G, Wang S, Pavlovic NM, Chan W (2024) Positive feedback mechanism in aristolochic acid I exposure-induced anemia and DNA adduct formation: implications for Balkan endemic nephropathy. J Agric Food Chem 72:18155\u201318161. https:\/\/doi.org\/10.1021\/acs.jafc.4c03508","DOI":"10.1021\/acs.jafc.4c03508"},{"key":"4297_CR10","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1038\/s41467-017-01358-x","volume":"8","author":"E Letouz\u00e9","year":"2017","unstructured":"Letouz\u00e9 E, Shinde J, Renault V, Couchy G, Blanc JF, Tubacher E, Bayard Q, Bacq D, Meyer V, Semhoun J, Bioulac-Sage P, Pr\u00e9v\u00f4t S, Azoulay D, Paradis V, Imbeaud S, Deleuze JF, Zucman-Rossi J (2017) Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat Commun 8:1315. https:\/\/doi.org\/10.1038\/s41467-017-01358-x","journal-title":"Nat Commun"},{"key":"4297_CR27","doi-asserted-by":"publisher","first-page":"118","DOI":"10.3390\/toxins15020118","volume":"15","author":"WL Li","year":"2023","unstructured":"Li WL, Padanilam BJ, Kim J (2023) The presence of testis determines aristolochic Acid-Induced nephrotoxicity in mice. Toxins 15:118. https:\/\/doi.org\/10.3390\/toxins15020118","journal-title":"Toxins"},{"key":"4297_CR7","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s13020-024-01003-y","volume":"19","author":"C Li","year":"2024","unstructured":"Li C, Li X, Niu M, Xiao D, Luo Y, Wang Y, Fang ZE, Zhan X, Zhao X, Fang M, Wang J, Xiao X, Bai Z (2024) Unveiling correlations between aristolochic acids and liver cancer: spatiotemporal heterogeneity phenomenon. Chin Med 19:132. https:\/\/doi.org\/10.1186\/s13020-024-01003-y","journal-title":"Chin Med"},{"key":"4297_CR36","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1021\/acs.chemrestox.8b00359","volume":"32","author":"Y Liu","year":"2019","unstructured":"Liu Y, Chan C, Jin L, Wong S, Chan W (2019) Quantitation of DNA adducts in target and nontarget organs of aristolochic acid I-exposed rats: correlating DNA adduct levels with organotropic activities. Chem Res Toxicol 32:397\u2013399. https:\/\/doi.org\/10.1021\/acs.chemrestox.8b00359","journal-title":"Chem Res Toxicol"},{"key":"4297_CR35","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/S0090-9556(25)07241-1","volume":"24","author":"LE Los","year":"1996","unstructured":"Los LE, Welsh DA, Herold EG, Bagdon WJ, Zacchei AG (1996) Gender differences in toxicokinetics, liver metabolism, and plasma esterase activity: observations from a chronic (27-week) toxicity study of enalapril\/diltiazem combinations in rats. Drug Metab Dispos 24:28\u201333. https:\/\/doi.org\/10.1016\/S0090-9556(25)07241-1","journal-title":"Drug Metab Dispos"},{"key":"4297_CR11","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1101\/507301","volume":"71","author":"ZN Lu","year":"2020","unstructured":"Lu ZN, Luo Q, Zhao LN, Shi Y, Wang N, Wang L, Han ZG (2020) The mutational features of aristolochic acid\u2013induced mouse and human liver cancers. Hepatol 71:929\u2013942. https:\/\/doi.org\/10.1101\/507301","journal-title":"Hepatol"},{"key":"4297_CR8","doi-asserted-by":"publisher","first-page":"eaan6446","DOI":"10.1126\/scitranslmed.aan6446","volume":"9","author":"AW Ng","year":"2017","unstructured":"Ng AW, Poon SL, Huang MN, Lim JQ, Boot A, Yu W, Suzuki Y, Thangaraju S, Ng CCY, Tan P, Pang ST, Huang HY, Yu MC, Lee PH, Hsieh SY, Chang AY, Teh BT, Rozen SG (2017) Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia. Sci Transl Med 9:eaan6446. https:\/\/doi.org\/10.1126\/scitranslmed.aan6446","journal-title":"Sci Transl Med"},{"key":"4297_CR45","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1096\/fj.13-233320","volume":"28","author":"CG Penaloza","year":"2014","unstructured":"Penaloza CG, Estevez B, Han DM, Norouzi M, Lockshin RA, Zakeri Z (2014) Sex-dependent regulation of cytochrome P450 family members Cyp1a1, Cyp2e1, and Cyp7b1 by methylation of DNA. FASEB J 28:966. https:\/\/doi.org\/10.1096\/fj.13-233320","journal-title":"FASEB J"},{"key":"4297_CR9","doi-asserted-by":"publisher","first-page":"197ra101","DOI":"10.1126\/scitranslmed.3006086","volume":"5","author":"SL Poon","year":"2013","unstructured":"Poon SL, Pang ST, McPherson JR, Yu W, Huang KK, Guan P, Weng WH, Siew EY, Liu Y, Heng HL, Chong SC, Gan A, Tay ST, Lim WK, Cutcutache I, Huang DH, Ler LD, Nairism\u00e4gi ML, Lee MH, Chang YH, Yu KJ, Waraporn C, Li BK, Yuan YF, Qian CN, Ng KF, Wu CF, Hsu CL, Bunte RM, Stratton MR, Futreal PA, Sung WK, Chuang CK, Ong CK, Rozen SG, Tan P, Teh BT (2013) Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci Transl Med 5:197ra101. https:\/\/doi.org\/10.1126\/scitranslmed.3006086","journal-title":"Sci Transl Med"},{"key":"4297_CR46","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1021\/tx200333g","volume":"25","author":"HA Priestap","year":"2012","unstructured":"Priestap HA, Torres MC, Rieger RA, Dickman KG, Freshwater T, Taft DR, Barbieri MA, Iden CR (2012) Aristolochic acid I metabolism in the isolated perfused rat kidney. Chem Res Toxicol 25:130\u2013139. https:\/\/doi.org\/10.1021\/tx200333g","journal-title":"Chem Res Toxicol"},{"key":"4297_CR26","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.3390\/molecules21101391","volume":"21","author":"M Shi","year":"2016","unstructured":"Shi M, Ma L, Zhou L, Fu P (2016) Renal protective effects of 17\u03b2-estradiol on mice with acute aristolochic acid nephropathy. Molecules 21:1391. https:\/\/doi.org\/10.3390\/molecules21101391","journal-title":"Molecules"},{"key":"4297_CR50","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1124\/dmd.107.014688","volume":"35","author":"S Shibutani","year":"2007","unstructured":"Shibutani S, Dong H, Suzuki N, Ueda S, Miller F, Grollman AP (2007) Selective toxicity of aristolochic acids I and II. Drug Metab Dispos 35:1217\u20131222. https:\/\/doi.org\/10.1124\/dmd.107.014688","journal-title":"Drug Metab Dispos"},{"key":"4297_CR48","doi-asserted-by":"publisher","first-page":"695","DOI":"10.2174\/1389200211314060006","volume":"14","author":"M Stiborova","year":"2013","unstructured":"Stiborova M, Martinek V, Frei E, Arlt VM, Schmeiser HH (2013) Enzymes metabolizing aristolochic acid and their contribution to the development of aristolochic acid nephropathy and urothelial cancer. Curr Drug Metab 14:695\u2013705. https:\/\/doi.org\/10.2174\/1389200211314060006","journal-title":"Curr Drug Metab"},{"key":"4297_CR47","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.3390\/ijms18102144","volume":"18","author":"M Stiborov\u00e1","year":"2017","unstructured":"Stiborov\u00e1 M, Arlt VM, Schmeiser HH (2017) DNA adducts formed by aristolochic acid are unique biomarkers of exposure and explain the initiation phase of upper urothelial cancer. Int J Mol Sci 18:2144. https:\/\/doi.org\/10.3390\/ijms18102144","journal-title":"Int J Mol Sci"},{"key":"4297_CR34","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1093\/ehjcvp\/pvw042","volume":"3","author":"J Tamargo","year":"2017","unstructured":"Tamargo J, Rosano G, Walther T, Duarte J, Niessner A, Kaski JC, Ceconi C, Drexel H, Kjeldsen K, Savarese G, Torp-Pedersen C, Atar D, Lewis BS, Agewall S (2017) Gender differences in the effects of cardiovascular drugs. Eur Heart J Cardiovasc Pharmacother 3:163\u2013182. https:\/\/doi.org\/10.1093\/ehjcvp\/pvw042","journal-title":"Eur Heart J :Cardiovasc Pharmacother"},{"key":"4297_CR38","doi-asserted-by":"publisher","first-page":"3223","DOI":"10.1021\/jf201987k","volume":"60","author":"L Tang","year":"2012","unstructured":"Tang L, Zhou J, Yang CH, Xia BJ, Hu M, Liu ZQ (2012) Systematic studies of sulfation and glucuronidation of 12 flavonoids in the mouse liver S9 fraction reveal both unique and shared positional preferences. J Agric Food Chem 60:3223\u20133233. https:\/\/doi.org\/10.1021\/jf201987k","journal-title":"J Agric Food Chem"},{"key":"4297_CR33","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/hr.2011.189","volume":"35","author":"K Ueno","year":"2012","unstructured":"Ueno K, Sato H (2012) Sex-related differences in pharmacokinetics and pharmacodynamics of anti-hypertensive drugs. Hypertens Res 35:245\u2013250. https:\/\/doi.org\/10.1038\/hr.2011.189","journal-title":"Hypertens Res"},{"key":"4297_CR29","unstructured":"United States Renal Data System (2023) USRDS Annual Data Report: Epidemiology of kidney disease in the United States. https:\/\/usrds-adr.niddk.nih.gov\/2023"},{"key":"4297_CR17","unstructured":"US Department of Health and Human Services and Food and Drug Administration (2001) FDA warns consumers to discontinue use of botanical products that contain aristolochic acid"},{"key":"4297_CR22","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/0140-6736(93)92984-2","volume":"341","author":"JL Vanherweghem","year":"1993","unstructured":"Vanherweghem JL, Tielemans C, Abramowicz D, Depierreux M, Anhaelen-Fastre R, Vanhaelen M, Dratwa M, Richard C, Vandervelde D, Verbeelen D, Jadoul M (1993) Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 341:387\u2013391. https:\/\/doi.org\/10.1016\/0140-6736(93)92984-2","journal-title":"Lancet"},{"key":"4297_CR28","doi-asserted-by":"publisher","first-page":"117240","DOI":"10.1016\/j.taap.2025.117240","volume":"496","author":"Q Wang","year":"2025","unstructured":"Wang Q, Hou J, Shui F, Tang J, Du J, Chen C, Zhang W, Tu MS, Li C, Mei Q (2025) Sex differences in aristolochic acid I-induced nephrotoxicity in mice and the effect of estradiol. Toxicol Appl Pharmacol 496:117240. https:\/\/doi.org\/10.1016\/j.taap.2025.117240","journal-title":"Toxicol Appl Pharmacol"},{"key":"4297_CR14","doi-asserted-by":"publisher","first-page":"112081","DOI":"10.1016\/j.biopha.2021.112081","volume":"142","author":"Z Xian","year":"2021","unstructured":"Xian Z, Tian J, Zhang Y, Meng J, Zhao Y, Li C, Yi Y, Han J, Liu S, Wang L, Pan C, Wang D, Wang F, Liang A (2021) Study on the potential nephrotoxicity and mutagenicity of aristolochic acid IVa and its mechanism. Biomed Pharmacother 142:112081. https:\/\/doi.org\/10.1016\/j.biopha.2021.112081","journal-title":"Biomed Pharmacother"},{"key":"4297_CR16","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/jcpt.12789","volume":"44","author":"HM Zhang","year":"2019","unstructured":"Zhang HM, Zhao XH, Sun ZH, Li GC, Liu GC, Sun LR, Hou JQ, Zhou W (2019) Recognition of the toxicity of aristolochic acid. J Clin Pharm Ther 44:157\u2013162. https:\/\/doi.org\/10.1111\/jcpt.12789","journal-title":"J Clin Pharm Ther"},{"key":"4297_CR32","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1021\/acs.chemrestox.2c00026","volume":"35","author":"J Zhang","year":"2022","unstructured":"Zhang J, Chan KKJ, Chan W (2022) Synergistic interaction of polycyclic aromatic hydrocarbons, phthalate esters, or phenol on DNA adduct formation by aristolochic acid I: insights into the etiology of Balkan endemic nephropathy. Chem Res Toxicol 35:849\u2013857. https:\/\/doi.org\/10.1021\/acs.chemrestox.2c00026","journal-title":"Chem Res Toxicol"},{"key":"4297_CR40","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1021\/acs.chemrestox.2c00370","volume":"36","author":"J Zhang","year":"2023","unstructured":"Zhang J, Chan CK, Pavlovic NM, Chan W (2023) Effects of diet on aristolochic acid-DNA adduct formation: implications for Balkan endemic nephropathy etiology. Chem Res Toxicol 36:438\u2013445. https:\/\/doi.org\/10.1021\/acs.chemrestox.2c00370","journal-title":"Chem Res Toxicol"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-025-04297-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-025-04297-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-025-04297-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T09:38:41Z","timestamp":1775036321000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-025-04297-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":53,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["4297"],"URL":"https:\/\/doi.org\/10.1007\/s00204-025-04297-5","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]},"assertion":[{"value":"2 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing financial interest","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}