TY - JOUR
T1 - Hydroxylated polychlorinated biphenyls selectively bind transthyretin in blood and inhibit amyloidogenesis
T2 - Rationalizing rodent PCB toxicity
AU - Purkey, Hans E.
AU - Palaninathan, Satheesh K.
AU - Kent, Kathleen C.
AU - Smith, Craig
AU - Safe, Stephen H.
AU - Sacchettini, James C.
AU - Kelly, Jeffery W.
N1 - Funding Information:
We thank Joel Buxbaum for helpful discussions and the National Institutes of Health grants DK46335, ESO9106, ESO4917, the Lita Annenberg Hazen Foundation, the Skaggs Institute of Chemical Biology, and a San Diego ARCS Foundation Fellowship (H.E.P.) for financial support of this work. J.W.K. is a cofounder of Fold Rx Pharmaceuticals, a company that is developing small-molecule amyloidogenesis inhibitors.
PY - 2004/12
Y1 - 2004/12
N2 - Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) are known to bind to transthyretin (TTR) in vitro, possibly explaining their bioaccumulation, rodent toxicity, and presumed human toxicity. Herein, we show that several OH-PCBs bind selectively to TTR in blood plasma; however, only one of the PCBs tested binds TTR in plasma. Some of the OH-PCBs displace thyroid hormone (T4) from TTR, rationalizing the toxicity observed in rodents, where TTR is the major T4 transporter. Thyroid binding globulin and albumin are the major T4 carriers in humans, making it unlikely that enough T4 could be displaced from TTR to be toxic. OH-PCBs are excellent TTR amyloidogenesis inhibitors in vitro because they bind to the TTR tetramer, imparting kinetic stability under amyloidogenic denaturing conditions. Four OH-PCB/TTR cocrystal structures provide further insight into inhibitor binding interactions.
AB - Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) are known to bind to transthyretin (TTR) in vitro, possibly explaining their bioaccumulation, rodent toxicity, and presumed human toxicity. Herein, we show that several OH-PCBs bind selectively to TTR in blood plasma; however, only one of the PCBs tested binds TTR in plasma. Some of the OH-PCBs displace thyroid hormone (T4) from TTR, rationalizing the toxicity observed in rodents, where TTR is the major T4 transporter. Thyroid binding globulin and albumin are the major T4 carriers in humans, making it unlikely that enough T4 could be displaced from TTR to be toxic. OH-PCBs are excellent TTR amyloidogenesis inhibitors in vitro because they bind to the TTR tetramer, imparting kinetic stability under amyloidogenic denaturing conditions. Four OH-PCB/TTR cocrystal structures provide further insight into inhibitor binding interactions.
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U2 - 10.1016/j.chembiol.2004.10.009
DO - 10.1016/j.chembiol.2004.10.009
M3 - Article
C2 - 15610856
AN - SCOPUS:10644265785
SN - 1074-5521
VL - 11
SP - 1719
EP - 1728
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 12
ER -