title: Global marine pollutants inhibit P-glycoprotein: Environmental levels, inhibitory effects, and cocrystal structure.
abstract: The world's oceans are a global reservoir of persistent organic pollutants to which humans and other animals are exposed. Although it is well known that these pollutants are potentially hazardous to human and environmental health, their impacts remain incompletely understood. We examined how persistent organic pollutants interact with the drug efflux transporter P-glycoprotein (P-gp), an evolutionarily conserved defense protein that is essential for protection against environmental toxicants. We identified specific congeners of organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers that inhibit mouse and human P-gp, and determined their environmental levels in yellowfin tuna from the Gulf of Mexico. In addition, we solved the cocrystal structure of P-gp bound to one of these inhibitory pollutants, PBDE (polybrominated diphenyl ether)-100, providing the first view of pollutant binding to a drug transporter. The results demonstrate the potential for specific binding and inhibition of mammalian P-gp by ubiquitous congeners of persistent organic pollutants present in fish and other foods, and argue for further consideration of transporter inhibition in the assessment of the risk of exposure to these chemicals.
authors.affiliation: Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093-0202, USA.
authors.forename: Sascha C T
authors.identifier: 0000-0003-3120-6485
authors.initials: SC
authors.lastname: Nicklisch
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093-0657, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rees
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093-0657, USA.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: McGrath
authors.affiliation: Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093-0202, USA.
authors.forename: Tufan
authors.initials: T
authors.lastname: Gökirmak
authors.affiliation: Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093-0202, USA.
authors.forename: Lindsay T
authors.initials: LT
authors.lastname: Bonito
authors.affiliation: Sekisui XenoTech, LLC, 1101 West Cambridge Circle Drive, Kansas City, KS 66103, USA.
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Vermeer
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093-0657, USA.
authors.forename: Cristina
authors.identifier: 0000-0002-1872-8425
authors.initials: C
authors.lastname: Cregger
authors.affiliation: Sekisui XenoTech, LLC, 1101 West Cambridge Circle Drive, Kansas City, KS 66103, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Loewen
authors.affiliation: Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093-0202, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Sandin
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093-0657, USA.; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093-0657, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Chang
authors.affiliation: Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093-0202, USA.
authors.forename: Amro
authors.initials: A
authors.lastname: Hamdoun
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004784:Environmental Monitoring; D055768:Halogenated Diphenyl Ethers / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000633:toxicity; D008800:Mexico; D051379:Mice; D009792:Oceans and Seas; D010575:Pesticides / Q000737:chemistry / Q000633:toxicity; D011487:Protein Conformation / Q000187:drug effects*; D014413:Tuna / Q000378:metabolism; D014877:Water Pollution, Chemical
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D055768:Halogenated Diphenyl Ethers; D006843:Hydrocarbons, Chlorinated; D010575:Pesticides