title: Exceptionally long-term persistence of DNA adducts formed by  carcinogenic aristolochic acid I in renal tissue from patients  with aristolochic acid nephropathy.
abstract: Aristolochic acid (AA) causes aristolochic acid nephropathy (AAN), first described in women in Belgium accidently prescribed Aristolochia fangchi in a slimming treatment, and also Balkan endemic nephropathy (BEN), through probable dietary contamination with Aristolochia clematitis seeds. Both nephropathies have a high risk of urothelial cancer, with AA being the causative agent. In tissues of AAN and BEN patients, a distinct DNA adduct, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), has been detected. DNA adducts can be removed through DNA repair, they can result in mutations through erroneous DNA replication or they can cause cell death. The dA-AAI adduct induces AT to TA transversions in the tumor-suppressor TP53 gene in experimental systems, matching TP53 mutations observed in urothelial tumors from AAN cancer cases. Using thin-layer chromatography 32P-postlabeling and mass spectrometric analysis we report the detection of dA-AAI in renal DNA from 11 Belgian AAN patients over 20 years after exposure to AA had ceased. Our results showed that dA-AAI is an established biomarker of AA exposure, and that this biomarker can be demonstrated to be persistent decades after a distinct AA exposure. Further, the persistence of dA-AAI adducts appears to be a critical determinant for the AA mutational fingerprint frequently found in oncogenes and tumor suppressor genes recently identified by whole genome sequencing of AA-associated urothelial tumors. The potential for exposure to AA worldwide is high; the unprecedented long-term persistence of dA-AAI provides a useful long-term biomarker of exposure and attests to the role of AA in human urothelial malignancy.
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.forename: Jöelle L
authors.initials: JL
authors.lastname: Nortier
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Gamboa da Costa
authors.forename: Jacques
authors.initials: J
authors.lastname: Sennesael
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Cassuto-Viguier
authors.forename: Damien
authors.initials: D
authors.lastname: Ambrosetti
authors.forename: Sandrine
authors.initials: S
authors.lastname: Rorive
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Pozdzik
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborova
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
mesh_terms: D000328:Adult; D000368:Aged; D034341:Aristolochic Acids / Q000009:adverse effects*; D001449:Balkan Nephropathy / Q000139:chemically induced*; D015415:Biomarkers / Q000032:analysis*; D002855:Chromatography, Thin Layer; D018736:DNA Adducts / Q000032:analysis*; D005260:Female; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009153:Mutagens / Q000009:adverse effects*
chemical_list: D034341:Aristolochic Acids; D015415:Biomarkers; D018736:DNA Adducts; D009153:Mutagens; C000228:aristolochic acid I