Zearalenone-14-Glucoside被细胞外基质中的β-葡萄糖苷酶水解为Zearalenone，在KGN细胞中发挥细胞内毒性,Toxins

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Zearalenone-14-Glucoside被细胞外基质中的β-葡萄糖苷酶水解为Zearalenone，在KGN细胞中发挥细胞内毒性
Toxins ( IF 3.9 ) Pub Date : 2022-07-04 , DOI: 10.3390/toxins14070458
Haonan Ruan ₁ , Yunyun Wang ₁ , Yong Hou ₁ , Jing Zhang ₁ , Jiashuo Wu ₁ , Fangqing Zhang ₁ , Ming Sui ₁ , Jiaoyang Luo ₁ , Meihua Yang ₁

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作为最重要的共轭真菌毒素之一，玉米赤霉烯酮-14-葡萄糖苷（Z14G）受到了研究人员的广泛关注。尽管Z14G在动物体内的代谢已被广泛研究，但Z14G的细胞内毒性和代谢过程尚未完全阐明。在本研究中，测定了 Z14G 对人卵巢颗粒细胞 (KGN) 的细胞毒性和 Z14G 在 KGN 细胞中的代谢。此外，通过共同给药β-葡萄糖苷酶和预先给药的β-葡萄糖苷酶抑制剂（Conduritol B epoxide，CBE）的实验来阐明Z14G毒性释放的机制。最后，利用人结肠腺癌细胞（Caco-2）代谢模型验证Z14G的毒性释放机制。结果表明，IC ₅₀Z14G 对 KGN 细胞的水解率为 420 μM，Z14G 在 ZEN 上的相对水解率为 35%（在 KGN 细胞中为 25% 细胞外和 10% 细胞内）。结果表明Z14G不能进入细胞，Z14G仅在细胞外被β-葡萄糖苷酶水解成其原型玉米赤霉烯酮（ZEN），在细胞内发挥毒性作用。总之，本研究证明了Z14G的细胞毒性，阐明了Z14G的毒性释放机制。与之前的研究结果不同，我们的结果表明 Z14G 不能进入细胞，而是通过去糖基化发挥细胞毒性。这项研究促进了 ZEN 及其代谢物的风险评估和立法限制的制定。

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Zearalenone-14-Glucoside Is Hydrolyzed to Zearalenone by β-Glucosidase in Extracellular Matrix to Exert Intracellular Toxicity in KGN Cells

As one of the most important conjugated mycotoxins, zearalenone-14-glucoside (Z14G) has received widespread attention from researchers. Although the metabolism of Z14G in animals has been extensively studied, the intracellular toxicity and metabolic process of Z14G are not fully elucidated. In this study, the cytotoxicity of Z14G to human ovarian granulosa cells (KGN) and the metabolism of Z14G in KGN cells were determined. Furthermore, the experiments of co-administration of β-glucosidase and pre-administered β-glucosidase inhibitor (Conduritol B epoxide, CBE) were used to clarify the mechanism of Z14G toxicity release. Finally, the human colon adenocarcinoma cell (Caco-2) metabolism model was used to verify the toxicity release mechanism of Z14G. The results showed that the IC₅₀ of Z14G for KGN cells was 420 μM, and the relative hydrolysis rate of Z14G on ZEN was 35% (25% extracellular and 10% intracellular in KGN cells). The results indicated that Z14G cannot enter cells, and Z14G is only hydrolyzed extracellularly to its prototype zearalenone (ZEN) by β-glucosidase which can exert toxic effects in cells. In conclusion, this study demonstrated the cytotoxicity of Z14G and clarified the toxicity release mechanism of Z14G. Different from previous findings, our results showed that Z14G cannot enter cells but exerts cytotoxicity through deglycosylation. This study promotes the formulation of a risk assessment and legislation limit for ZEN and its metabolites.

更新日期：2022-07-04

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