Inhibitory effects of environmental chemicals on protein disulfide isomerase in vitro.
BACKGROUND
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.


METHODS
We examined the effects of 22 suspected EDC on both the T3-binding activity and isomerase activity of rat recombinant PDI.


RESULTS
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.


CONCLUSIONS
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.
Okada
Kazushi
K
Department of Chemical Biology, Osaka City University, Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
Hiroi
Toyoko
T
Imaoka
Susumu
S
Funae
Yoshihiko
Y
D000818:Animals; D001559:Benzhydryl Compounds; D002733:Chlorophenols / Q000494:pharmacology; D052244:Endocrine Disruptors / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity; D008297:Male; D010416:Pentachlorophenol / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology*; D011075:Polybrominated Biphenyls / Q000494:pharmacology; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014285:Triiodothyronine, Reverse / Q000378:metabolism; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D002733:Chlorophenols; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D010416:Pentachlorophenol; D010636:Phenols; D011075:Polybrominated Biphenyls; D019704:Protein Disulfide-Isomerases; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D014285:Triiodothyronine, Reverse; C080417:4-octylphenol; C020806:tetrabromobisphenol A; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C004762:2,4-dichlorophenol