Aristolochic acid mutagenesis: molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer

Abstract

Balkan endemic nephropathy (BEN) is found in certain rural areas of the Balkans and affects at least 25,000 inhabitants. Of the many hypotheses on BEN, the Aristolochia hypothesis has recently gained ground substantiated by the investigations on aristolochic acid nephropathy (AAN). On both clinical and morphological grounds, AAN is very similar to BEN. That exposure to aristolochic acid (AA) of individuals living in endemic areas through consumption of bread made with flour contaminated with seeds of Aristolochia clematitis is responsible for BEN is an old hypothesis, but one which is fully consistent with the unique epidemiologic features of BEN. Here, we propose an approach to investigate AA-induced mutagenesis in BEN that can provide molecular clues to the aetiology of its associated urothelial cancer. The molecular mechanism of AA-induced carcinogenesis demonstrates a strong association between DNA adduct formation, mutation pattern and tumour development. A clear link between urothelial tumours, p53 mutations and AA exposure should emerge as more tumour DNA from BEN patients from different endemic areas becomes available for mutation analysis. We predict that the observed p53 mutation spectrum will be dominated by AT --> TA transversion mutations as has already been demonstrated in the human p53 gene of immortalized cells after exposure to AAI and urothelial tumours from BEN patients in Croatia. Moreover, the detection of AA-specific DNA adducts in renal tissue of a number of BEN patients and individuals living in areas endemic for BEN in Croatia provides new evidence that chronic exposure to AA is a risk factor for BEN and its associated cancer.

Gene expression profiles modulated by the human carcinogen aristolochic acid I in human cancer cells and their dependence on TP53

“…Moreover, a high frequency of AT→TA transversion mutations was found in the TP53 of urothelial tumours from patients with Balkan endemic nephropathy and exposed to AA (Grollman et al, 2007). These data indicate that TP53 plays an important role in the molecular mechanism whereby AA causes urothelial cancer (Arlt et al, 2007b). In HCT116 cells exposed to benzo(a)pyrene (BaP) DNA adduct formation was also dependent on TP53, being significantly lower in p53-null than in p53-WT cells (Hockley et al, 2008), suggesting that basal levels of TP53 are linked to the metabolic activation of both BaP and AAI.…”

“…AAI-DNA adducts have been linked with specific AT→TA transversion mutations in codon 61 of the H-ras gene leading to activation of this oncogene in AAI-induced tumours in rodents (Schmeiser et al, 1990;Arlt et al, 2000). The same type of mutation was found in TP53 in urothelial tumour cells of an AAN patient (Lord et al, 2004), suggesting that TP53 is mutated in AAN-associated tumours (Arlt et al, 2001b;Arlt et al, 2007b). Furthermore, AT→TA transversions were found in TP53 of immortalised cells derived from murine primary human TP53 knock-in (Hupki) embryonic fibroblasts exposed to AAI (Liu et al, 2004;Feldmeyer et al, 2006;vom Brocke et al, 2006).…”

The Role of Biotransformation Enzymes in the Development of Renal Injury and Urothelial Cancer Caused by Aristolochic Acid: Urgent Questions and Difficult Answers

“…In contrast to the suggestion that AA might be the direct cause of the interstitial nephropathy, metabolic activation of AA to species forming DNA adducts is an important step in AA-induced malignant transformation 24,25 . Indeed, the molecular mechanism of AA-induced carcinogenesis demonstrates strong association between DNA adduct formation, mutation pattern and tumor development 24,30,31 . The DNA adduct 7-(deoxyadenosin-N 6 -yl)aristolactam I (dA-AAI) (Fig.…”

“…Others suggest that metabolic activation of AA to species forming DNA adducts is not the only important step for AA-induced malignant transformation 24,25 but that specific DNA damage also leads to cell-specific alterations at the protein transcriptional level and this might impair physiological processes [26][27][28][29] . In contrast to the suggestion that AA might be the direct cause of the interstitial nephropathy, metabolic activation of AA to species forming DNA adducts is an important step in AA-induced malignant transformation 24,25 . Indeed, the molecular mechanism of AA-induced carcinogenesis demonstrates strong association between DNA adduct formation, mutation pattern and tumor development 24,30,31 .…”

β-Naphthoflavone protects mice from aristolochic acid-I-induced acute kidney injury in a CYP1A dependent mechanism

“…Since the first observation in Belgium in 1993 [5] , more than 200 cases of AA-induced nephropathy (AAN) have been identified worldwide [6] . AA is also suspected as an etiologic factor for Balkan endemic nephropathy (BEN) [7] , which shares many clinic and histological characteristics with AAN [8] and affects at least 25 000 inhabitants in certain rural areas of the Balkan [9] . However, there is no effective therapeutics for AAN due to the poor understanding of the mechanism of AA-induced kidney toxicity [10] .…”