Okada Kazushi, Hiroi Toyoko, Imaoka Susumu, Funae Yoshihiko
Department of Chemical Biology, Osaka City University, Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
Osaka City Med J. 2005 Dec;51(2):51-63.
The influence of endocrine disrupting chemicals (EDCs) upon physiological functions and their mechanisms is of concern. We have previously demonstrated that protein disulfide isomerase (PDI) was a target molecule of bisphenol A (BPA), which is considered to be EDC. PDI plays a key role in protein folding as an isomerase and also possesses a 3,3',5-triiodo-L-thyronine (T3)-binding activity. Since PDI activities were inhibited by BPA in our previous study, BPA might have adverse effects on physiological functions via the inhibition of PDI activities. We conducted this study to identify the compounds which disturb PDI activities as well as BPA, and to discuss their structural characteristics.
We examined the effects of 22 suspected EDC on both the T3-binding activity and isomerase activity of rat recombinant PDI.
Among the 22 compounds, only phenolic compounds, namely BPA, p-octylphenol, p-nonylphenol, 2,4-dichlorophenol, pentachlorophenol, tetrabromobisphenol A, and tetrachlorobisphenol A, inhibited T3 binding to PDI. Furthermore non-halogenated compounds among these phenolic compounds, such as BPA, p-octylphenol, and p-nonylphenol, showed inhibitory effects on the isomerase activity of PDI.
Our results suggest that phenolic groups might have important inhibitory effects on the T3-binding activity of PDI, and that compounds with phenolic groups might have the same effects on PDI. Furthermore, non-halogenated phenolic compounds had inhibitory effects on the isomerase activities of PDI in addition to T3-binding activity, indicating that these compounds might also have adverse effects on protein folding, which PDI participates in by catalyzing rearrangements of disulfide bonds as an isomerase.
内分泌干扰化学物质（EDCs）对生理功能的影响及其作用机制备受关注。我们之前已证明蛋白二硫键异构酶（PDI）是双酚A（BPA）的靶分子，双酚A被认为是一种内分泌干扰化学物质。PDI作为一种异构酶在蛋白质折叠过程中起关键作用，并且还具有三碘甲状腺原氨酸（T3）结合活性。由于在我们之前的研究中PDI活性受到双酚A的抑制，双酚A可能通过抑制PDI活性对生理功能产生不利影响。我们开展本研究以鉴定出与双酚A一样干扰PDI活性的化合物，并探讨它们的结构特征。
我们检测了22种疑似内分泌干扰化学物质对大鼠重组PDI的T3结合活性和异构酶活性的影响。
在这22种化合物中，只有酚类化合物，即双酚A、对辛基苯酚、对壬基苯酚、2,4 - 二氯苯酚、五氯苯酚、四溴双酚A和四氯双酚A，抑制T3与PDI的结合。此外，这些酚类化合物中的非卤代化合物，如双酚A、对辛基苯酚和对壬基苯酚，对PDI的异构酶活性也有抑制作用。
我们的结果表明酚基可能对PDI的T3结合活性具有重要抑制作用，并且具有酚基的化合物可能对PDI有相同影响。此外，非卤代酚类化合物除了对T3结合活性有抑制作用外，还对PDI的异构酶活性有抑制作用，这表明这些化合物可能也会对蛋白质折叠产生不利影响，而PDI作为异构酶通过催化二硫键重排参与蛋白质折叠过程。
