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-N 6 -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 32 P-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 longterm biomarker of exposure and attests to the role of AA in human urothelial malignancy.

Risk assessment of plant food supplements and other herbal products containing aristolochic acids using the margin of exposure (MOE) approach

“…Of the 18 PFS analysed, three samples (16.7%) tested positive and contained both AAI and AAII at levels that ranged from 2.1 to 594.8 and from 0.6 to 235.3 µg g -1 respectively (Table 2). For all these PFS, the level of AAI was 2.5-3.5-fold higher than AAII, supporting the fact that AAI is a major component in Aristolochia species (Schmeiser et al 1996;Stiborová et al 2003). Among the three positive samples, S2 (plant leaf) had the highest AA levels, followed by S9 (tincture) and S4 (globule).…”

Aristolochic Acid Induced Suicidal Erythrocyte Death

“…Possibly, Ca 2+ entry and ceramide production contribute to the known stimulation of kidney cell apoptosis [4,25,. In nucleated cells, Aristolochic Acid is, however, at least partially effective by further mechanisms, such as formation of DNA adducts [71]. Erythrocytes are devoid of nuclei and thus would not be affected by DNA adduct forming activities.…”

In vitro genotoxicity tests point to an unexpected and harmful effect of a Magnolia and Aristolochia association

“…Genotoxicity arises from their metabolization into aristolactams (ALs) that form covalent DNA adducts with the DNA bases dG or dA (Heinrich et al 2009;Zhou et al 2013). Such DNA damages are probably implicated in the acute fibrosis observed in AAN patients; they have more recently been associated with a high risk of urothelial cancer and, surprisingly, have been detected in the DNA of patients for more than 20 years after AAs exposure (Schmeiser et al 2014). When improperly repaired, these DNA lesions lead to a characteristic A:T to T:A transversion mutation (Grollman et al 2007).…”