p53 mutations as fingerprints for aristolochic acid – an environmental carcinogen in endemic (Balkan) nephropathy

Abstract

The activation of protooncogenes and inactivation of tumor suppressor genes are considered to be the main molecular events in the multistep process of carcinogenesis. Mutations of the TP53 tumor suppressor gene have been found in nearly all tumor types and are estimated to contribute to more than 50% of all cancers. Most mutations lead to the synthesis of highly stable, inactive proteins that accumulate in the nucleus of cancer cells. Among the 393 codons of the human p53 gene, 222 are targets of 698 different types of mutations. Alterations of codons 175, 248, 273 and 282 correspond to 19 % of all mutations and are considered general hot spot mutations. Dietary exposure to aristolochic acid (AA), an established nephrotoxin and human carcinogen found in all Aristolochia species was shown to be the causative agent of aristolochic acid nephropathy (previously called Chinese herbs nephropathy). This syndrome is characterized by proximal tubular damage, renal interstitial fibrosis, slow progression to the end stage renal disease and a high prevalence of upper urinary tract urothelial carcinoma (otherwise a highly unusual location). AA preferentially binds to purines in DNA and is associated with a high frequency of A → T transversions in the p53 gene. Rats treated with AA develop A:T → T:A mutations in codon 61. The pathological and clinical features of endemic (Balkan) nephropathy closely resemble those associated with aristolochic acid nephropathy except for the slower progression to end stage renal disease and longer cumulative period before the appearance of urothelial cancer. Recently, we reported the presence of AA-DNA adducts in renal cortex and A → T p53 mutations in tumor tissue of patients from Croatia and Bosnia with endemic nephropathy. These data support the hypothesis that dietary exposure to AA is a major risk factor for endemic (Balkan) nephropathy.

Could Disappearance of Endemic (Balkan) Nephropathy Be Expected in Forthcoming Decades?

“…The difference among various endemic foci could result, as already mentioned, from the use of different diagnostic criteria, or might reflect differences in activity of the environmental toxic agent. Our recent studies clearly demonstrate that in Bosnia and Herzegovina, Croatia and Serbia, aristolochic acid is a causative agent [8][9][10][11]13] . Information on the decreasing number of EN patients is important for public health authorities and for future projections as it could be presumed that the need for renal replacement therapy, at least due to EN, would be reduced in this region.…”

Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies

“…58 These mutations showed a remarkable correspondence with the mutations found in tumor of patients with Balkan endemic nephropathy, supporting the claim that this plant carcinogen has a direct role in the etiology of this regional disease. 59 Another mouse model of mutant p53 GOF was presented by Deppert (L3). In this model, transgenic mice carrying the SV40 early region were crossed with mice carrying mutant p53.…”

«Suspects» in Etiology of Endemic Nephropathy: Aristolochic Acid versus Mycotoxins

“…An analysis of p53 mutations in AA-treated rats showed that predominant mutation was an A:T®T:A transversion [20]. Such a mutation, which accounted for 78% of all base substitutions, was also found in EN-associated UTT patients from Croatia and Bosnia, which supports the implication of AA in EN [20,57]. In contrast, in a study of blood samples of 90 Bulgarian EN patients, these p53 mutations were found only in 10% of the samples [58].…”