scholarly journals Ochratoxin A and Aristolochic Acid Involvement in Nephropathies and Associated Urothelial Tract Tumours

2009 ◽  
Vol 60 (4) ◽  
pp. 465-483 ◽  
Author(s):  
Annie Pfohl-Leszkowicz
Keyword(s):  
Ochratoxin A ◽  
Aristolochic Acid ◽  
Adduct Formation ◽  
Dna Adduct ◽  
Balkan Endemic Nephropathy ◽  
Aristolochic Acids ◽  
The World ◽  
Main Culprit ◽  
Endemic Nephropathy

Ochratoxin A and Aristolochic Acid Involvement in Nephropathies and Associated Urothelial Tract TumoursThis review addresses the unresolved aetiology of several nephropathies and associated upper tract tumours diagnosed all over the world, but especially in the Balkan regions. Studies conducted over the last 35 years point to mycotoxins, mainly ochratoxin A (OTA) as the main culprit. Recent theories however have implicated aristolochic acids (AA). The aim of this review is to put forward arguments in favour of the mycotoxin theory and to show the incoherence of the AA theory. It discusses the differences between the epidemiology of Balkan endemic nephropathy (BEN) and aristolochic acid nephropathy (AAN); OTA and AA carcinogenicity; clinical and pathological effects induced by OTA and AA; sources of OTA contamination (food, air, drinking water); OTA- and AA-DNA adduct formation; the role of genetic polymorphisms; and the risk for young children.

scholarly journals Co-Exposure to Aristolochic Acids I and II Increases DNA Adduct Formation Responsible for Aristolochic Acid I-Mediated Carcinogenicity in Rats

2021 ◽  
Vol 22 (19) ◽  
pp. 10479
Author(s):  
František Bárta ◽  
Alena Dedíková ◽  
Michaela Bebová ◽  
Šárka Dušková ◽  
Jaroslav Mráz ◽  
...  
Keyword(s):  
Plant Extract ◽  
Aristolochic Acid ◽  
Adduct Formation ◽  
Dna Adduct ◽  
Renal Diseases ◽  
Balkan Endemic Nephropathy ◽  
Chemical Research ◽  
Aristolochic Acids ◽  
Endemic Nephropathy

The plant extract aristolochic acid (AA), containing aristolochic acids I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases associated with upper urothelial cancer. Recently (Chemical Research in Toxicology 33(11), 2804–2818, 2020), we showed that the in vivo metabolism of AAI and AAII in Wistar rats is influenced by their co-exposure (i.e., AAI/AAII mixture). Using the same rat model, we investigated how exposure to the AAI/AAII mixture can influence AAI and AAII DNA adduct formation (i.e., AA-mediated genotoxicity). Using 32P-postlabelling, we found that AA-DNA adduct formation was increased in the livers and kidneys of rats treated with AAI/AAII mixture compared to rats treated with AAI or AAII alone. Measuring the activity of enzymes involved in AA metabolism, we showed that enhanced AA-DNA adduct formation might be caused partially by both decreased AAI detoxification as a result of hepatic CYP2C11 inhibition during treatment with AAI/AAII mixture and by hepatic or renal NQO1 induction, the key enzyme predominantly activating AA to DNA adducts. Moreover, our results indicate that AAII might act as an inhibitor of AAI detoxification in vivo. Consequently, higher amounts of AAI might remain in liver and kidney tissues, which can be reductively activated, resulting in enhanced AAI DNA adduct formation. Collectively, these results indicate that AAII present in the plant extract AA enhances the genotoxic properties of AAI (i.e., AAI DNA adduct formation). As patients suffering from AAN and BEN are always exposed to the plant extract (i.e., AAI/AAII mixture), our findings are crucial to better understanding host factors critical for AAN- and BEN-associated urothelial malignancy.

scholarly journals Molecular Markers in Upper Urothelial Carcinoma Associated to Balkan Endemic Nephropathy. Aristolochic Acid as the Major Risk Factor of the Worldwide Disease

2009 ◽  
Vol 9 ◽  
pp. 1360-1373 ◽  
Author(s):  
Ljubinka Jankovic Velickovic ◽  
Takanori Hattori ◽  
Vladisav Stefanovic
Keyword(s):  
Regression Analysis ◽  
Urothelial Carcinoma ◽  
Growth Stage ◽  
Aristolochic Acid ◽  
Balkan Endemic Nephropathy ◽  
Specific Cell ◽  
Ki 67 ◽  
High Stage ◽  
Endemic Nephropathy

The role of aristolochic acid in the etiology of Balkan endemic nephropathy (BEN) and associated upper urothelial carcinoma (UUC) was recently confirmed. The aim of this study was to determine the marker(s) specific for BEN-associated UUC. A total of 82 patients with UUC (38 from the BEN region and 44 control tumors) were included in the study. The Ki-67 index in BEN tumors correlated with the grade and multifocality (p< 0.05), but in regression analysis, only the grade of BEN tumor. The p53 index was significantly higher in BEN than in control tumors (p< 0.05), as well as the alteration of p53 (p< 0.05). BEN low-stage tumors, tumors without limphovascular invasion (LVI), and tumors of the renal pelvis had a higher p53 index than the control tumors (p< 0.05, 0.01, 0.05, respectively). The Ki-67 index was higher in control tumors with high-stage and solid growth than in BEN UUC (p < 0.050, 0.005). The Ki-67 correlated with the grade, growth, stage, LVI, and multifocality of UUC on the best way, but not with the group. In regression analysis, only multifocality of UUC had predictive influence on Ki-67 activity (p< 0.001). P53 correlated with the grade, growth, and group (p< 0.05). This investigation identifies the p53 pathway as the specific cell cycle marker involved in BEN-associated UUC.

The influence of ochratoxin A on DNA adduct formation by the carcinogen aristolochic acid in rats

2014 ◽  
Vol 89 (11) ◽  
pp. 2141-2158 ◽  
Author(s):  
Marie Stiborová ◽  
František Bárta ◽  
Kateřina Levová ◽  
Petr Hodek ◽  
Eva Frei ◽  
...  
Keyword(s):  
Ochratoxin A ◽  
Aristolochic Acid ◽  
Adduct Formation ◽  
Dna Adduct

Karyomegaly of tubular kidney cells in human chronic interstitial nephropathy in Tunisia: respective role of Ochratoxin a and possible genetic predisposition

2004 ◽  
Vol 23 (7) ◽  
pp. 339-346 ◽  
Author(s):  
Wafa Hassen ◽  
Salwa Abid-Essafi ◽  
Abdellatif Achour ◽  
Noureddine Guezzah ◽  
Abdelfettah Zakhama ◽  
...  
Keyword(s):  
Ochratoxin A ◽  
Food Samples ◽  
Balkan Endemic Nephropathy ◽  
Unknown Aetiology ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Endemic Nephropathy ◽  
Interstitial Nephropathy ◽  
Renal Tubular

Karyomegalic nephropathy associated to bizarre enlargement of nuclei in renal tubular epithelial cells was first described by Mihatch in 1979. We present herein additional cases occurring in three siblings suffering from chronic interstitial nephropathy (CIN) of unknown aetiology where the renal biopsies showed numerous enlarged and hyperchromatic nuclei. CIN of unknown aetiology has been previously characterized and showed striking similarities with Balkan Endemic Nephropathy (BEN). Ochratoxin A (OTA) is a nephrotoxic mycotoxin suspected to be the causal agent of the BEN as well as the Tunisian CIN of unknown aetiology. OTA is incriminated in the onset of these disclosed cases of karyomegalic nephropathy since high OTA concentrations were found in blood (505.83 ng/ml, 102.63 ng/ml and 1023 ng/ml) and in urine (94.40 ng/ml and 10.18 ng/ml) of two of them. Moreover, we have investigated OTA in blood and urine as well as in food samples of the entire household (21 people). Our findings suggest (i) a link between OTA and the outcome of this karyomegalic nephropathy, and (ii) the possible involvement of a genetic factor since the three cases have the same haplotype B27/35.

scholarly journals Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid

2019 ◽  
Vol 39 (3) ◽  
pp. 284-296 ◽  
Author(s):  
Bojan Jelaković ◽  
Živka Dika ◽  
Volker M. Arlt ◽  
Marie Stiborova ◽  
Nikola M. Pavlović ◽  
...  
Keyword(s):  
Aristolochic Acid ◽  
Balkan Endemic Nephropathy ◽  
Causative Role ◽  
Endemic Nephropathy

scholarly journals Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse

2011 ◽  
Vol 300 (6) ◽  
pp. F1360-F1367 ◽  
Author(s):  
Thomas A. Rosenquist
Keyword(s):  
Proximal Tubule ◽  
Genetic Predisposition ◽  
Aristolochic Acid ◽  
Herbal Remedies ◽  
Balkan Endemic Nephropathy ◽  
Traditional Medicines ◽  
Aristolochic Acids ◽  
F2 Population ◽  
Endemic Nephropathy ◽  
Upper Urothelial Cancer

Aristolochic acids (AA) are plant-derived nephrotoxins and carcinogens found in traditional medicines and herbal remedies. AA causes aristolochic acid nephropathy (AAN) and is a suspected environmental agent in Balkan endemic nephropathy (BEN) and its associated upper urothelial cancer. Approximately 5–10% of individuals exposed to AA develop renal insufficiency and/or cancer; thus a genetic predisposition to AA sensitivity has been proposed. The mouse is an established animal model of AAN, and inbred murine strains vary in AA sensitivity, confirming the genetic predisposition. We mapped quantitative trait loci (QTL) correlated with proximal tubule dysfunction after exposure to AA in an F2 population of mice, derived from breeding an AA-resistant strain ( C57BL/6J) and an AA-sensitive strain ( DBA/2J). A single main QTL was identified on chromosome 4 ( Aanq1); three other interacting QTLs, ( Aanq2–4) also were detected. The Aanq1 region was also detected in untreated mice, raising the possibility that preexisting differences in proximal tubule function may affect the severity of AA-elicited toxicity. This study lays the groundwork for identifying the genetic pathways contributing to AA sensitivity in the mouse and will further our understanding of human susceptibility to AA found widely in traditional medicines.

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