Okratoksin A i omjer sfinganina i sfingozina u urinu stanovnika s područja endemske nefropatije u Hrvatskoj

The most plausible theory of the aetiology of endemic nephropathy links it with exposure to nephrotoxic mycotoxin ochratoxin A (OTA). In this study, the concentration of OTA and sphinganine/sphingosine (Sa/So) ratio, the biomarker of another nephrotoxic mycotoxin fumonisin B1 exposure, were analysed in 45 human urine samples collected in the endemic village of Kaniža in Croatia and in 18 samples from control village. Samples were collected twice from the same persons in 2000 and 2005. In both years the frequency of OTA-positive samples was higher in Kaniža (43 % and 18 %, respectively) than in the control village (28 % and 6 %, respectively). OTA concentrations in samples collected in Kaniža were higher in 2000 than in 2005 (p1 at the same time, while in Kaniža four such samples were collected in 2000 and one in 2005.Najprihvatljivija teorija o etiologiji endemske nefropatije povezuje njezin nastanak s izloženošću nefrotoksičnim mikotoksinima. Dok se izloženost mikotoksinu okratoksinu A (OTA) može dokazati njegovim nalazom u biološkim uzorcima kao što su krv i urin, vrlo kratko zadržavanje fumonizina B1 (FB1) u organizmu to onemogućava. Na pokusnim je životinjama nađeno da je porast omjera koncentracija sfi ngolipida sfi nganina i sfi ngozina (Sa/So) biološki pokazatelj izloženosti tom mikotoksinu. U ovom istraživanju mjerena je koncentracija OTA i omjer koncentracija Sa/So u urinu 45 stanovnika u endemskom selu Kaniža i 18 stanovnika u kontrolnom selu. Uzorci urina skupljeni su od istih osoba 2000. i 2005. godine. U obje godine učestalost uzoraka koji su sadržavali OTA bila je veća u Kaniži (43 % i 18 %) negoli u kontrolnom selu (28 % i 6 %). Koncentracija OTA također je bila viša u urinima skupljenim u Kaniži negoli u kontrolnom selu. Koncentracija OTA u uzorcima skupljenim u Kaniži 2000. bila je viša nego u uzorcima iz 2005. (p<0.005). Iako je u urinima iz obje godine omjer koncentracija Sa/So bio viši u Kaniži negoli u kontrolnom selu, razlika nije bila statistički značajna. Nije nađen nijedan uzorak skupljen u kontrolnom selu koji bi istodobno sadržavao mjerljivu koncentraciju OTA i omjer Sa/So veći od jedan. Za razliku od uzoraka iz kontrolnog sela, četiri uzorka skupljena u Kaniži u 2000. godini i jedan uzorak u 2005. godini upućivali su na istodobnu izloženost ovim mikotoksinima

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

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