Bisphenol A binds to protein disulfide isomerase and inhibits its enzymatic and hormone-binding activities.
Bisphenol A [2,2-bis-(4-hydroxyphenyl) propane; BPA] is a versatile industrial material for plastic products, but is increasingly being recognized as a pervasive industrial pollutant as well. Accumulating evidence indicates that the environmental contaminant BPA is one of the endocrine-disrupting chemicals that potentially can adversely affect humans as well as wildlife. To define the molecular aspects of BPA action, we first investigated the molecules with which it physically interacts. High BPA-binding activity was detected in the P2 membrane fraction prepared from rat brains. As determined by SDS-PAGE analysis, the molecular mass of a BPA-binding protein purified from the rat brain P2 fraction was 53 kDa. The N-terminal amino acid sequence of the purified BPA-binding protein was identical with that of the rat protein disulfide isomerase (PDI), which is a multifunctional protein that is critically involved in the folding, assembly, and shedding of many cellular proteins via its isomerase activity in addition to being considered to function as an intracellular hormone reservoir. The Kd value of BPA binding to recombinant rat PDI was 22.6 +/- 6.6 microm. Importantly, the binding activity of L-T3 and 17beta-estradiol hormones to PDI was competitively inhibited by BPA in addition to abolishing its isomerase activities. In this paper we report that the ubiquitous and multifunctional protein PDI is a target of BPA and propose that binding to PDI and subsequent inhibition of PDI activity might be mechanistically responsible for various actions of BPA.
Hiroi
Toyoko
T
Department of Chemical Biology, Osaka City University Medical School, Osaka 545-8585, Japan.
Okada
Kazushi
K
Imaoka
Susumu
S
Osada
Mayuko
M
Funae
Yoshihiko
Y
D000818:Animals; D001559:Benzhydryl Compounds; D002352:Carrier Proteins / Q000302:isolation & purification / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D008297:Male; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism*; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D002352:Carrier Proteins; D004958:Estradiol; D010636:Phenols; D019704:Protein Disulfide-Isomerases; D011994:Recombinant Proteins; D014284:Triiodothyronine; C006780:bisphenol A; D000098826:Bisphenol A Compounds