{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:11:54Z","timestamp":1790838714415,"version":"4.1.0"},"reference-count":110,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Grantov\u00e1 Agentura \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["18-10251S"],"award-info":[{"award-number":["18-10251S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The plant extract aristolochic acid (AA), containing aristolochic acids I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases associated with upper urothelial cancer. Recently (Chemical Research in Toxicology 33(11), 2804\u20132818, 2020), we showed that the in vivo metabolism of AAI and AAII in Wistar rats is influenced by their co-exposure (i.e., AAI\/AAII mixture). Using the same rat model, we investigated how exposure to the AAI\/AAII mixture can influence AAI and AAII DNA adduct formation (i.e., AA-mediated genotoxicity). Using 32P-postlabelling, we found that AA-DNA adduct formation was increased in the livers and kidneys of rats treated with AAI\/AAII mixture compared to rats treated with AAI or AAII alone. Measuring the activity of enzymes involved in AA metabolism, we showed that enhanced AA-DNA adduct formation might be caused partially by both decreased AAI detoxification as a result of hepatic CYP2C11 inhibition during treatment with AAI\/AAII mixture and by hepatic or renal NQO1 induction, the key enzyme predominantly activating AA to DNA adducts. Moreover, our results indicate that AAII might act as an inhibitor of AAI detoxification in vivo. Consequently, higher amounts of AAI might remain in liver and kidney tissues, which can be reductively activated, resulting in enhanced AAI DNA adduct formation. Collectively, these results indicate that AAII present in the plant extract AA enhances the genotoxic properties of AAI (i.e., AAI DNA adduct formation). As patients suffering from AAN and BEN are always exposed to the plant extract (i.e., AAI\/AAII mixture), our findings are crucial to better understanding host factors critical for AAN- and BEN-associated urothelial malignancy.<\/jats:p>","DOI":"10.3390\/ijms221910479","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T21:38:09Z","timestamp":1632865089000},"page":"10479","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Co-Exposure to Aristolochic Acids I and II Increases DNA Adduct Formation Responsible for Aristolochic Acid I-Mediated Carcinogenicity in Rats"],"prefix":"10.3390","volume":"22","author":[{"given":"Franti\u0161ek","family":"B\u00e1rta","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Ded\u00edkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Bebov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0160\u00e1rka","family":"Du\u0161kov\u00e1","sequence":"additional","affiliation":[{"name":"Centre of Occupational Health, National Institute of Public Health, \u0160rob\u00e1rova 48, 100 42 Prague 10, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslav","family":"Mr\u00e1z","sequence":"additional","affiliation":[{"name":"Centre of Occupational Health, National Institute of Public Health, \u0160rob\u00e1rova 48, 100 42 Prague 10, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz H.","family":"Schmeiser","sequence":"additional","affiliation":[{"name":"Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker M.","family":"Arlt","sequence":"additional","affiliation":[{"name":"Department of Analytical, Environmental and Forensic Sciences Division, King\u2019s College London, 150 Stamford Street, London SE1 9NH, UK"},{"name":"Toxicology Department, GAB Consulting GmbH, Heinrich-Fuchs-Str. 96, 69126 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Hodek","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5430-4403","authenticated-orcid":false,"given":"Marie","family":"Stiborov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.jep.2009.05.028","article-title":"Local Uses of Aristolochia Species and Content of Nephrotoxic Aristolochic Acid 1 and 2-A Global Assessment Based on Bibliographic Sources","volume":"125","author":"Heinrich","year":"2009","journal-title":"J. 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