Hydroxylated polychlorinated biphenyls (PCBs) interact with protein disulfide isomerase and inhibit its activity.
Protein disulfide isomerase (PDI) is a catalyst of isomerization of substrate protein intra- and extra-molecular disulfide bridges and also has 3,3',5-triiodo-l-thyronine (T(3))-binding activity and molecular chaperone-like activity. We previously found that halogenated derivatives of bisphenol A as well as bisphenol A itself bind to PDI and thereby suppress the oxidative refolding of reduced RNaseA by PDI. Polychlorinated biphenyls (PCBs) are environmental endocrine-disrupting chemicals that cause various abnormalities in many organs such as the central nervous system. PCBs are metabolized to hydroxylated compounds (HO-PCBs) in humans and other animals, and HO-PCBs gain toxicity by metabolism. In the present study, 2',3,3',4',5'-pentachlorobiphenyl (penCB), 2',3,3',5,5',6'-hexachlorobiphenyl (hexCB), and their 4-hydroxylated metabolites (HO-penCB and HO-hexCB, respectively) were used to examine whether they interact with PDI and inhibit its activity. HO-penCB and HO-hexCB markedly inhibited the binding of T(3) to PDI. However, nonhydroxylated PCBs did not show any interaction with PDI. The effects of PCBs and HO-PCBs on PDI activity were also investigated using an RNaseA refolding assay. Both HO-PCBs inhibited the oxidative refolding of reduced RNaseA by PDI. We also assessed the effects of HO-PCBs and PCBs on the chaperone activity of PDI, which was measured by a thermal aggregation assay, and found that neither HO-PCBs nor PCBs have significant inhibitory or promoting effects. These findings suggest that the metabolites of PCBs have the potential to cause defective protein folding via PDI.
Okada
Kazushi
K
Nanobiotechnology Research Center and Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan. bhp46831@kwansei.ac.jp
Hashimoto
Shoko
S
Funae
Yoshihiko
Y
Imaoka
Susumu
S
D000818:Animals; D045744:Cell Line, Tumor; D006900:Hydroxylation; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017510:Protein Folding; D051381:Rats
D011078:Polychlorinated Biphenyls; D019704:Protein Disulfide-Isomerases