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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.
AuthorsHeinz H Schmeiser, Jöelle L Nortier, Rajinder Singh, Gonçalo Gamboa da Costa, Jacques Sennesael, Elisabeth Cassuto-Viguier, Damien Ambrosetti, Sandrine Rorive, Agnieszka Pozdzik, David H Phillips, Marie Stiborova, Volker M Arlt
JournalInternational journal of cancer (Int J Cancer) Vol. 135 Issue 2 Pg. 502-7 (Jul 15 2014) ISSN: 1097-0215 [Electronic] United States
PMID24921086 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Aristolochic Acids
  • Biomarkers
  • DNA Adducts
  • Mutagens
  • aristolochic acid I
Topics
  • Adult
  • Aged
  • Aristolochic Acids (adverse effects)
  • Balkan Nephropathy (chemically induced)
  • Biomarkers (analysis)
  • Chromatography, Thin Layer
  • DNA Adducts (analysis)
  • Female
  • Humans
  • Kidney (chemistry, pathology)
  • Male
  • Mass Spectrometry
  • Middle Aged
  • Mutagens (adverse effects)

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