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Popp, Tanja, Balszuweit, Frank, Schmidt, Annette, Eyer, Florian, Thiermann, Horst and Steinritz, Dirk (2020): Assessment of alpha-amanitin toxicity and effects of silibinin and penicillin in different in vitro models. In: Toxicology in Vitro, Vol. 67, 104921

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Silibinin (Sil) is used as hepatoprotective drug and is approved for therapeutic use in amanitin poisoning. In our study we compared Sil-bis-succinate (Sil(BS)), a water-soluble drug approved for i.v.-administration, with Sil solved in ethanol (Sil(EtOH)), which is normally used in research. We challenged monocultures or 3D-microtissues consisting of HepG2 cells or primary hepatocytes with alpha-amanitin and treated with SILBS, SILEtOH, penicillin and combinations thereof. Cell viability and the integrity of the microtissues was monitored. Finally, the expression of the transporters OATP1B1 and B3 was analyzed by qRT-PCR. We demonstrated that primary hepatocytes were more sensitive to alpha-amanitin compared to HepG2. Primary hepatocytes cultures were protected by Sil(BS) and Sil(EtOH) independent of penicillin from the cytotoxic effects of alpha-amanitin. Subsequent studies of the expression profile of the transporters OATP1B1/B3 revealed that primary hepatocytes do express both whereas in HepG2 cells they were hardly detectable. Our study showed that Sil(BS) has significant advantage over Sil(EtOH) with no additional benefit of penicillin. Moreover, HepG2 cells may not represent an appropriate model to investigate Amanita phalloides poisoning in vitro with focus on OATP transporters since these cells are lacking sensitivity towards alpha-amanitin probably due to missing cytotoxicity-associated transporters suggesting that primary hepatocytes should be preferred in this context.

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