Wednesday, April 27, 2016
Global marine pollutants
Persistent organic pollutants (POPs) are hazardous, man-made chemicals that endure in the environment and bioaccumulate in animals. Their environmental persistence ensues from properties such as halogenation and hydrophobicity that slow degradation and promote partitioning into organisms. At the same time, these properties also favor POP bioaccumulation by slowing their elimination. Indeed, although all animals have numerous metabolic enzymes, conjugation systems, and transporter proteins that normally act to eliminate xenobiotics, these systems appear ineffective at limiting POP bioaccumulation.
A critical step toward understanding the persistence and organismal impacts of POPs is defining their interactions with xenobiotic elimination systems. Drug transporters are plasma membrane proteins that both limit the entry of foreign chemicals into the body and speed their clearance, and are already well studied for their roles in drug disposition (1). Previous studies have suggested that environmental chemicals can also interact with drug transporters, such as P-glycoprotein (P-gp), but that they are poorly transported, and that these interactions ultimately lead to inhibition of transporter function (2–10). Of concern is that this inhibition reduces the efficacy of transport, thereby sensitizing animals to toxic chemicals that would otherwise be effluxed (11, 12).
Here, we took a multilevel approach to examine transporter-pollutant interactions, from levels in the environment down to the cocrystal structure of an environmental chemical bound to the transporter. We focused on P-gp, an adenosine triphosphate (ATP)–binding cassette (ABC) transporter (13–15), which plays a major role in the disposition of xenobiotics (1, 16) and which is one of the best-studied drug transporters to date. P-gp has a large binding pocket that interacts with a wide variety of structurally divergent hydrophobic molecules (16–19), and binding within this large pocket can have different impacts on the transporter, from stimulation to inhibition of function (20, 21). P-gp is conserved and is typically expressed at environmental barrier tissues, such as the small intestine or gills (22–24).
To identify POPs that interact with P-gp, we used robust biochemical and cellular assays of mouse and human P-gp and identified specific congeners that inhibit this transporter. Using x-ray crystallography, we validated the binding of one of these chemicals, polybrominated diphenyl ether (PBDE)–100, deep within the ligand pocket of the transporter, providing the first snapshots of P-gp bound to a pollutant. To gain insight into the environmental relevance of P-gp inhibitors, we measured their levels in yellowfin tuna (Thunnus albacares) from the Gulf of Mexico (GOM) and used these data to examine the effects of a representative POP mixture on the transport function of the human P-gp.