PURPOSE OF REVIEW: To acquaint urologists with aristolochic acid nephropathy, an iatrogenic disease that poses a distinct threat to global public health. In China alone, 100 million people may currently be at risk. We illustrate the power of molecular epidemiology in establishing the cause of this disease. RECENT FINDINGS: Molecular epidemiologic approaches and novel mechanistic information established a causative linkage between exposure to aristolochic acid and urothelial carcinomas of the bladder and upper urinary tract. Noninvasive tests are available that detect urothelial cancers through the genetic analysis of urinary DNA. Combined with cytology, some of these tests can detect 95% of patients at risk of developing bladder and/or upper urothelial tract cancer. Robust biomarkers, including DNA-adduct and mutational signature analysis, unequivocally identify aristolochic acid-induced tumours. The high mutational load associated with aristolochic acid-induced tumours renders them candidates for immune-checkpoint therapy. SUMMARY: Guided by recent developments that facilitate early detection of urothelial cancers, the morbidity and mortality associated with aristolochic acid-induced bladder and upper tract urothelial carcinomas may be substantially reduced. The molecular epidemiology tools that define aristolochic acid-induced tumours may be applicable to other studies assessing potential environmental carcinogens.

• MeSH
• adukty DNA genetika   metabolismus   MeSH
• balkánská nefropatie chemicky indukované   MeSH
• karcinogeny MeSH
• kyseliny aristolochové toxicita   MeSH
• léky rostlinné čínské škodlivé účinky   MeSH
• lidé MeSH
• nádory močového měchýře chemicky indukované   MeSH
• urologické nádory chemicky indukované   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Balkan endemic nephropathy (BEN) is a unique, chronic renal disease frequently associated with upper urothelial cancer (UUC). It only affects residents of specific farming villages located along tributaries of the Danube River in Bosnia-Herzegovina, Croatia, Macedonia, Serbia, Bulgaria, and Romania where it is estimated that ~100,000 individuals are at risk of BEN, while ~25,000 have the disease. This review summarises current findings on the aetiology of BEN. Over the last 50 years, several hypotheses on the cause of BEN have been formulated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecular epidemiological studies provide a strong case that chronic dietary exposure to aristolochic acid (AA) a principal component of Aristolochia clematitis which grows as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still enigmatic features of BEN that need to be resolved is why the prevalence of BEN is only 3-7 %. This suggests that individual genetic susceptibilities to AA exist in humans. In fact dietary ingestion of AA along with individual genetic susceptibility provides a scenario that plausibly can explain all the peculiarities of BEN such as geographical distribution and high risk of urothelial cancer. For the countries harbouring BEN implementing public health measures to avoid AA exposure is of the utmost importance because this seems to be the best way to eradicate this once mysterious disease to which the residents of BEN villages have been completely and utterly at mercy for so long.

• MeSH
• Aristolochia chemie   růst a vývoj   toxicita   MeSH
• balkánská nefropatie chemicky indukované   epidemiologie   patofyziologie   prevence a kontrola   MeSH
• dieta škodlivé účinky   MeSH
• endemické nemoci * MeSH
• faktory vyvracející (epidemiologie) MeSH
• karcinogeny životního prostředí analýza   toxicita   MeSH
• kontaminace potravin * prevence a kontrola   MeSH
• kyseliny aristolochové analýza   toxicita   MeSH
• ledviny účinky léků   patofyziologie   MeSH
• léková rezistence MeSH
• lidé MeSH
• medicína založená na důkazech * MeSH
• mouka škodlivé účinky   analýza   MeSH
• plevel chemie   růst a vývoj   toxicita   MeSH
• prevalence MeSH
• pšenice růst a vývoj   MeSH
• riziko MeSH
• semena rostlinná růst a vývoj   MeSH
• urologické nádory chemicky indukované   epidemiologie   patofyziologie   prevence a kontrola   MeSH
• zemědělské plodiny růst a vývoj   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• východní Evropa epidemiologie   MeSH

Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. Individual susceptibility to AA-induced disease likely reflects individual differences in enzymes that metabolize AA. Herein, we evaluated AAI metabolism by human cytochrome P450 (CYP) 1A1 and 1A2 in two CYP1A-humanized mouse lines that carry functional human CYP1A1 and CYP1A2 genes in the absence of the mouse Cyp1a1/1a2 orthologs. Human and mouse hepatic microsomes and human CYPs were also studied. Human CYP1A1 and 1A2 were found to be principally responsible for reductive activation of AAI to form AAI-DNA adducts and for oxidative detoxication to 8-hydroxyaristolochic acid (AAIa), both in the intact mouse and in microsomes. Overall, AAI-DNA adduct levels were higher in CYP1A-humanized mice relative to wild-type mice, indicating that expression of human CYP1A1 and 1A2 in mice leads to higher AAI bioactivation than in mice containing the mouse CYP1A1 and 1A2 orthologs. Furthermore, an exclusive role of human CYP1A1 and 1A2 in AAI oxidation to AAIa was observed in human liver microsomes under the aerobic (i.e., oxidative) conditions. Because CYP1A2 levels in human liver are at least 100-fold greater than those of CYP1A1 and there exists a > 60-fold genetic variation in CYP1A2 levels in human populations, the role of CYP1A2 in AAI metabolism is clinically relevant. The results suggest that, in addition to CYP1A1 and 1A2 expression levels, in vivo oxygen concentration in specific tissues might affect the balance between AAI nitroreduction and demethylation, which in turn would influence tissue-specific toxicity or carcinogenicity.

• MeSH
• adukty DNA metabolismus   MeSH
• cytochrom P-450 CYP1A1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• cytosol enzymologie   MeSH
• dealkylace MeSH
• inhibitory cytochromu P450 CYP1A2 MeSH
• inhibitory enzymů farmakologie   MeSH
• jaterní mikrozomy enzymologie   MeSH
• játra účinky léků   enzymologie   MeSH
• karcinogeny metabolismus   toxicita   MeSH
• kyseliny aristolochové metabolismus   toxicita   moč   MeSH
• lidé MeSH
• metabolická inaktivace MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši transgenní MeSH
• myši MeSH
• oxidace-redukce MeSH
• rekombinantní proteiny metabolismus   MeSH
• urologické nádory chemicky indukované   MeSH
• urotel účinky léků   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA may also cause another type of kidney fibrosis with malignant transformation of the urothelium, called Balkan Endemic Nephropathy (BEN). The compound predominantly responsible for the nephropathy and urothelial cancer of AA, is aristolochic acid I (AAI) which is a genotoxic mutagen after metabolic activation The activation pathway involves reduction of the nitro group to a cyclic N-acylnitrenium ion that can form covalent DNA adducts. These specific DNA adducts have been detected in experimental animals exposed to AAI, and in urothelial tissues from AAN patients. In rodent tumours induced by AAI, 7-(deoxyadenosin-N(6)-yl)aristolactam I was the most abundant DNA adduct formed and associated with activation of ras oncogenes through a characteristic transversion mutation. Such A:T-->T:A mutations have been identified in TP53 of urothelial tumour DNA of an AAN patient and in several patients suffering from BEN along with specific AA-DNA adducts. Understanding which enzymes are involved in AAI activation to species forming DNA adducts and/or detoxification to its O-demethylated metabolite aristolochic acid Ia (AAIa) is important in order to assess susceptibility to this carcinogen. METHODS AND RESULTS: A literature search. CONCLUSIONS: The most important human enzymes activating AAI by simple nitroreduction in vitro are hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase, hepatic microsomal cytochrome P450 (CYP) 1A2 and renal microsomal NADPH:CYP reductase as well as cyclooxygenase which is highly expressed in urothelial tissue. However, the contribution of most of these enzymes to the development of AAN and BEN diseases is still unclear. Hepatic CYP enzymes were found to detoxify AAI to AAIa in mice, and thereby protect the kidney from injury. CYP enzymes of the 1A subfamily seem to play a major role in this process in mouse liver. Likewise, among human CYP enzymes, CYP1A1 and 1A2 were found to be the most efficient enzymes participating in AAI oxidation to AAIa in vitro. Nevertheless, which CYPs are the most important in this process in both animal models and in humans have not been entirely resolved as yet. In addition, the relative contribution of enzymes found to activate AAI to species responsible for induction of urothelial cancer in humans remains still to be resolved.

• MeSH
• adukty DNA metabolismus   MeSH
• aktivace enzymů MeSH
• biotransformace MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• cytochrom P-450 CYP1A2 metabolismus   MeSH
• financování organizované MeSH
• kyseliny aristolochové farmakokinetika   toxicita   MeSH
• ledviny účinky léků   MeSH
• lidé MeSH
• myši MeSH
• NADPH-cytochrom c-reduktasa metabolismus   MeSH
• nemoci ledvin chemicky indukované   MeSH
• urologické nádory chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

Ingestion of aristolochic acid (AA) is associated with the development of AA-nephropathy and Balkan endemic nephropathy, which are characterized by chronic renal failure, tubulointerstitial fibrosis, and urothelial cancer. Understanding which enzymes are involved in AA activation and/or detoxification is important in assessing susceptibility to AA. Xiao et al. demonstrate that hepatic cytochrome P450s in mice detoxicate AA and thereby protect kidney from injury. The relative contribution of enzymes activating AA to induce urothelial cancer in humans remains to be resolved.

• MeSH
• játra enzymologie   MeSH
• karcinogeny metabolismus   toxicita   MeSH
• kyseliny aristolochové metabolismus   toxicita   MeSH
• metabolická inaktivace MeSH
• myši MeSH
• NADPH-cytochrom c-reduktasa genetika   metabolismus   MeSH
• nemoci ledvin enzymologie   chemicky indukované   MeSH
• urologické nádory enzymologie   chemicky indukované   MeSH
• urotel MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• komentáře MeSH