is one of the deadliest mushrooms worldwide, causing most fatal cases of mushroom poisoning. Among the poisonous substances of , amanitins are the most lethal toxins to humans. Currently, there are no specific antidotes available for managing amanitin poisoning and treatments are lack of efficacy. Amanitin mainly causes severe injuries to specific organs, such as the liver, stomach, and kidney, whereas the lung, heart, and brain are hardly affected. However, the molecular mechanism of this phenomenon remains not understood. To explore the possible mechanism of organ specificity of amanitin-induced toxicity, eight human cell lines derived from different organs were exposed to α, β, and γ-amanitin at concentrations ranging from 0.3 to 100 μM. We found that the cytotoxicity of amanitin differs greatly in various cell lines, among which liver-derived HepG2, stomach-derived BGC-823, and kidney-derived HEK-293 cells are most sensitive. Further mechanistic study revealed that the variable cytotoxicity is mainly dependent on the different expression levels of the organic anion transporting polypeptide 1B3 (OATP1B3), which facilitates the internalization of amanitin into cells. Besides, knockdown of OATP1B3 in HepG2 cells prevented α-amanitin-induced cytotoxicity. These results indicated that OATP1B3 may be a crucial therapeutic target against amanitin-induced organ failure.

中文翻译：

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鹅膏蕈素在不同细胞系中诱导的不同细胞毒性是由 OATP1B3 的不同表达水平介导的

是世界上最致命的蘑菇之一，导致蘑菇中毒死亡病例最多。在有毒物质中，鹅膏蕈碱是对人类最致命的毒素。目前，尚无治疗鹅膏蕈碱中毒的特效解毒剂，且治疗方法缺乏疗效。鹅膏蕈碱主要对肝脏、胃、肾等特定器官造成严重损伤，而肺、心脏和大脑则几乎不受影响。然而，这种现象的分子机制仍不清楚。为了探索鹅膏蕈碱诱导毒性的器官特异性的可能机制，将来自不同器官的八种人类细胞系暴露于浓度范围为0.3至100μM的α、β和γ-鹅膏蕈碱。我们发现鹅膏蕈碱的细胞毒性在不同细胞系中差异很大，其中肝源性HepG2、胃源性BGC-823和肾源性HEK-293细胞最敏感。进一步的机制研究表明，不同的细胞毒性主要取决于有机阴离子转运多肽1B3（OATP1B3）的不同表达水平，其促进鹅膏蕈碱内化到细胞中。此外，HepG2 细胞中 OATP1B3 的敲低可防止 α-鹅膏蕈碱诱导的细胞毒性。这些结果表明 OATP1B3 可能是针对鹅膏蕈碱诱导的器官衰竭的重要治疗靶点。