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多学科方法揭示了未被探索的黄曲霉毒素 B1 在严重损害维生素 D 作用机制中的作用。

A multidisciplinary approach disclosing unexplored Aflatoxin B1 roles in severe impairment of vitamin D mechanisms of action.

机构信息

Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, Naples, Italy.

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Sergio Pansini, Naples, Italy.

出版信息

Cell Biol Toxicol. 2023 Aug;39(4):1275-1295. doi: 10.1007/s10565-022-09752-y. Epub 2022 Sep 6.

DOI:10.1007/s10565-022-09752-y
PMID:36066700
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10425525/
Abstract

Aflatoxin B1 (AFB1), produced by fungi of the genus Aspergillus, is the most toxic and carcinogenic mycotoxin among the classes of aflatoxins. Previous research showed that AFB1 affects vitamin D receptor (VDR) expression. In the present study, integrated computational and experimental studies were carried out to investigate how AFB1 can interfere with Vitamin D signalling. A competitive antagonism of AFB1 toward RXRα and VDR was hypothesized by comparing the docked complex of AFB1/RXRα and AFB1/VDR ligand-binding domain (LBD) with the X-ray structures of RXRα and VDR bound to known ligands. Accordingly, we demonstrated that AFB1 can affect vitamin D-mediated transcriptional activation of VDR by impairing the formation of protein complexes containing both VDR-RXRα and RXRα/RAR and affecting the subcellular localization of VDR and RXRα. As a whole, our data indicate that AFB1 can interfere with different molecular pathways triggered by vitamin D with an antagonistic mechanism of action.

摘要

黄曲霉毒素 B1（AFB1）是由黄曲霉属真菌产生的，是所有黄曲霉毒素中最具毒性和致癌性的一种。之前的研究表明，AFB1 会影响维生素 D 受体（VDR）的表达。在本研究中，通过比较 AFB1/RXRα 和 AFB1/VDR 配体结合域（LBD）与已知配体结合的 RXRα 和 VDR 的 X 射线结构，进行了整合计算和实验研究，以探究 AFB1 如何干扰维生素 D 信号。假设 AFB1 对 RXRα 和 VDR 具有竞争性拮抗作用。因此，我们证明 AFB1 可以通过破坏包含 VDR-RXRα 和 RXRα/RAR 的蛋白质复合物的形成以及影响 VDR 和 RXRα 的细胞内定位来影响维生素 D 介导的 VDR 转录激活。总的来说，我们的数据表明，AFB1 可以通过拮抗作用机制干扰维生素 D 触发的不同分子途径。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e84b/10425525/fcdfc0e27f62/10565_2022_9752_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e84b/10425525/890c1ae195b6/10565_2022_9752_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e84b/10425525/5af113abeeb5/10565_2022_9752_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e84b/10425525/314b368267c6/10565_2022_9752_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e84b/10425525/482bf6593d5c/10565_2022_9752_Fig10_HTML.jpg
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