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.
- Klíčová slova
- Aristolochic acid, Aristolochic acid nephropathy, Balkan endemic nephropathy, Disease aetiology, Environmental and genetic factors, Upper urothelial cancer,
- 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
- Názvy látek
- aristolochic acid I MeSH Prohlížeč
- karcinogeny životního prostředí MeSH
- kyseliny aristolochové MeSH
OBJECTIVES: The herbal drug aristolochic acid (AA) derived from Aristolochia species has been shown to be the cause of aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and their urothelial malignancies. One of the common features of AAN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumor development. One cause for these different responses may be individual differences in the activities of the enzymes catalyzing the biotransformation of AA. Thus, the identification of enzymes principally involved in the metabolism of AAI, the major toxic component of AA, and detailed knowledge of their catalytic specificities is of major importance. Human cytochrome P450 (CYP) 1A1 and 1A2 enzymes were found to be responsible for the AAI reductive activation to form AAI-DNA adducts, while its structurally related analogue, CYP1B1 is almost without such activity. However, knowledge of the differences in mechanistic details of CYP1A1-, 1A2-, and 1B1- mediated reduction is still lacking. Therefore, this feature is the aim of the present study. METHODS: Molecular modeling capable of evaluating interactions of AAI with the active site of human CYP1A1, 1A2 and 1B1 under the reductive conditions was used. In silico docking, employing soft-soft (flexible) docking procedure was used to study the interactions of AAI with the active sites of these human enzymes. RESULTS: The predicted binding free energies and distances between an AAI ligand and a heme cofactor are similar for all CYPs evaluated. AAI also binds to the active sites of CYP1A1, 1A2 and 1B1 in similar orientations. The carboxylic group of AAI is in the binding position situated directly above heme iron. This ligand orientation is in CYP1A1/1A2 further stabilized by two hydrogen bonds; one between an oxygen atom of the AAI nitro-group and the hydroxyl group of Ser122/Thr124; and the second bond between an oxygen atom of dioxolane ring of AAI and the hydroxyl group of Thr497/Thr498. For the CYP1B1:AAI complex, however, any hydrogen bonding of the nitro-group of AAI is prevented as Ser122/Thr124 residues are in CYP1B1 protein replaced by hydrophobic residue Ala133. CONCLUSION: The experimental observations indicate that CYP1B1 is more than 10× less efficient in reductive activation of AAI than CYP1A2. The docking simulation however predicts the binding pose and binding energy of AAI in the CYP1B1 pocket to be analogous to that found in CYP1A1/2. We believe that the hydroxyl group of S122/T124 residue, with its polar hydrogen placed close to the nitro group of the substrate (AAI), is mechanistically important, for example it could provide a proton required for the stepwise reduction process. The absence of a suitable proton donor in the AAI-CYP1B1 binary complex could be the key difference, as the nitro group is in this complex surrounded only by the hydrophobic residues with potential hydrogen donors not closer than 5 Å.
- MeSH
- adukty DNA chemie metabolismus MeSH
- Aristolochia chemie MeSH
- aromatické hydroxylasy chemie genetika metabolismus MeSH
- chemické modely MeSH
- cytochrom P-450 CYP1A1 chemie genetika metabolismus MeSH
- cytochrom P-450 CYP1A2 chemie genetika metabolismus MeSH
- cytochrom P450 CYP1B1 MeSH
- hydrofobní a hydrofilní interakce účinky léků MeSH
- katalytická doména účinky léků MeSH
- kyseliny aristolochové škodlivé účinky chemie farmakokinetika MeSH
- léky rostlinné čínské škodlivé účinky chemie farmakokinetika MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- nemoci ledvin chemicky indukované MeSH
- nitroreduktasy škodlivé účinky chemie farmakokinetika MeSH
- počítačová simulace MeSH
- sekvence aminokyselin MeSH
- terciární struktura proteinů účinky léků MeSH
- vodíková vazba účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adukty DNA MeSH
- aristolochic acid I MeSH Prohlížeč
- aromatické hydroxylasy MeSH
- CYP1A1 protein, human MeSH Prohlížeč
- CYP1A2 protein, human MeSH Prohlížeč
- CYP1B1 protein, human MeSH Prohlížeč
- cytochrom P-450 CYP1A1 MeSH
- cytochrom P-450 CYP1A2 MeSH
- cytochrom P450 CYP1B1 MeSH
- kyseliny aristolochové MeSH
- léky rostlinné čínské MeSH
- nitroreduktasy MeSH
