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Vrednotenje zdravilnih učinkovin in okoljskih onesnažil kot modulatorjev receptorja za aril ogljikovodike (AhR)
Smontara, Tjaša (Author), Jakopin, Žiga (Mentor) More about this mentor... This link opens in a new window

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Abstract
Receptor za aril ogljikovodike (AhR) veže številne strukturno različne ligande, in sicer različne naravne endogene in eksogene spojine ter nekatere zdravilne učinkovine in okoljska onesnažila. Nekaterim izmed teh spojin smo zato lahko izpostavljeni med zdravljenjem ali preko okolja. Najprej smo z literaturnim pregledom in pregledom baz podatkov naredili nabor zdravilnih učinkovin in okoljskih onesnažil, ki se vežejo na receptor AhR. Nato smo raziskali, pri kakšnih koncentracijah izkazujejo te spojine modulatorne učinke na AhR in jih primerjali s koncentracijami, katerim smo dejansko lahko izpostavljeni. Ugotovili smo, da lahko sedem zdravilnih učinkovin, in sicer ketokonazol, leflunomid, omeprazol, ciprofibrat, tiabendazol, niklozamid in nitazoksanid, ki imajo dokazano modulatorno delovanje na receptor AhR, modulira AhR pri terapevtskih koncentracijah. Med 27 testiranimi okoljskimi onesnažili jih lahko le šest modulira AhR pri plazemskih koncentracijah, izmerjenih pri izpostavljenih ljudeh, in sicer PCB 126, benzo[a]piren, dehidroimidakloprid, pentaklorofenol, bentazon in diuron. Ugotovili smo tudi, da le ena proučevana komponenta izdelkov za osebno nego, ki smo ji izpostavljeni prek mil, zobnih past in deodorantov, modulira receptor AhR pri realnih pogojih izpostavljenosti, medtem ko lahko trije izmed proučevanih naravnih ligandov, med katere spadajo resveratrol, kampferol in piperin, pri realnih pogojih izpostavljenosti modulirajo receptor AhR. S pomočjo programa VirtualToxLab, ki omogoča vrednotenje sposobnosti spojin za vezavo na AhR in silico, smo na koncu izračunali še vezavne afinitete teh spojin na preiskovan receptor in ugotovili, da rezultati večinoma ne kolerirajo z izmerjenimi vrednostmi. Ključne ugotovitve magistrske naloge kažejo torej na to, da lahko številne spojine, katerim smo izpostavljeni hote (zdravilne učinkovine, naravne spojine iz prehrane, komponente izdelkov za osebno nego) kot tudi nehote (okoljska onesnažila), modulirajo nivo aktivacije receptorja AhR in na ta način povzročajo raznolike učinke, predvsem v gastrointestinalnem traktu, imunskem sistemu in centralnem živčnem sistemu.

Language:Slovenian
Keywords:receptor za aril ogljikovodike (AhR), ligandi AhR, zdravilne učinkovine, okoljska onesnažila, VirtualToxLab
Work type:Master's thesis/paper (mb22)
Organization:FFA - Faculty of Pharmacy
Year:2020
Views:608
Downloads:241
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Secondary language

Language:English
Title:Evaluation of pharmaceuticals and environmental pollutants as aryl hydrocarbon receptor (AhR) modulators
Abstract:
The aryl hydrocarbon receptor (AhR) binds many structurally different ligands including natural endogenous and exogenous compounds, as well as certain active pharmaceutical substances and environmental pollutants. We can be potentially exposed to some of these compounds during medical treatments or through the environment. First, we conducted a review of the literature and databases to make a selection of active pharmaceutical substances and environmental pollutants known to modulate AhR activity. We then investigated at what concentrations these compounds exert modulatory effects on AhR and compared them to the concentrations to which we may actually be exposed. We discovered that seven active substances, namely ketoconazole, leflunomide, omeprazole, ciprofibrate, thiabendazole, niclosamide and nitazoxanide, with experimentally determined AhR activity, can modulate AhR at therapeutic plasma concentrations. Only six environmental pollutants of 27 tested, can modulate AhR at plasma concentrations measured in exposed humans, namely PCB 126, benzo[a]pyrene, dehydroimidacloprid, pentachlorophenol, bentazone and diuron. We also discovered that only one of the studied components of personal care products to which we are exposed via soaps, toothpastes and deodorants is able to modulate the AhR receptor under realistic exposure conditions. The three natural ligands that can modulate the AhR receptor under realistic exposure conditions are resveratrol, kaempferol, and coumestrol. We calculated the binding of these compounds using the VirtualToxLab, which enables in silico assessment of AhR-binding capacity of compounds, we calculated the binding affinities of these compounds to the investigated receptor and found that the results mostly do not correlate with the experimental values determined in vitro. The findings obtained within the scope of this Master's thesis indicate that many compounds to which we are exposed both intentionally (pharmaceutical drugs, natural compounds from our diet, components of personal care products) as well as unintentionally (environmental pollutants) modulate the level of AhR activation. As a result, they have the potential to cause many diverse effects, particularly in the gastrointestinal tract, the immune system and the central nervous system.

Keywords:aryl hydrocarbon receptor (AhR), AhR ligands, active pharmaceutical substances, environmental pollutants, VirtualToxLab

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