Hydroxylated Polychlorinated Biphenyls Selectively Bind Transthyretin in Blood and Inhibit Amyloidogenesis: Rationalizing Rodent PCB Toxicity | Academic Article individual record
abstract

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.

author list (cited authors)
Purkey, H. E., Palaninathan, S. K., Kent, K. C., Smith, C., Safe, S. H., Sacchettini, J. C., & Kelly, J. W.
publication date
2004
publisher
Elsevier BV Publisher
published in
keywords
  • Structure-Activity Relationship
  • Humans
  • Prealbumin
  • Amyloid
  • Models, Molecular
  • Protein Binding
  • Ligands
  • Molecular Structure
  • Animals
  • Crystallography, X-Ray
  • Polychlorinated Biphenyls
altmetric score

12.0

citation count

91