title: Killing them with kindness? In-hive medications may inhibit xenobiotic efflux transporters and endanger honey bees.
abstract: BACKGROUND
  Honey bees (Apis mellifera) have recently experienced higher than normal overwintering colony losses. Many factors have been evoked to explain the losses, among which are the presence of residues of pesticides and veterinary products in hives. Multiple residues are present at the same time, though most often in low concentrations so that no single product has yet been associated with losses. Involvement of a combination of residues to losses may however not be excluded. To understand the impact of an exposure to combined residues on honey bees, we propose a mechanism-based strategy, focusing here on Multi-Drug Resistance (MDR) transporters as mediators of those interactions.
  
  
  RESULTS
  Using whole-animal bioassays, we demonstrate through inhibition by verapamil that the widely used organophosphate and pyrethroid acaricides coumaphos and τ-fluvalinate, and three neonicotinoid insecticides: imidacloprid, acetamiprid and thiacloprid are substrates of one or more MDR transporters. Among the candidate inhibitors of honey bee MDR transporters is the in-hive antibiotic oxytetracycline. Bees prefed oxytetracycline were significantly sensitized to the acaricides coumaphos and τ-fluvalinate, suggesting that the antibiotic may interfere with the normal excretion or metabolism of these pesticides.
  
  
  CONCLUSIONS
  Many bee hives receive regular treatments of oxytetracycline and acaricides for prevention and treatment of disease and parasites. Our results suggest that seasonal co-application of these medicines to bee hives could increase the adverse effects of these and perhaps other pesticides. Our results also demonstrate the utility of a mechanism-based strategy. By identifying pesticides and apicultural medicines that are substrates and inhibitors of xenobiotic transporters we prioritize the testing of those chemical combinations most likely to result in adverse interactions.
authors.affiliation: Department of Entomology, University of Maryland, College Park, Maryland, United States of America. djh@umd.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Hawthorne
authors.forename: Galen P
authors.initials: GP
authors.lastname: Dively
mesh_terms: D000818:Animals; D001516:Bees; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018432:Drug Resistance, Multiple; D056727:Endangered Species; D010118:Oxytetracycline / Q000008:administration & dosage*; D014700:Verapamil / Q000008:administration & dosage*; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D015262:Xenobiotics; D014700:Verapamil; D010118:Oxytetracycline
references.citation: Pest Manag Sci. 2008 Nov;64(11):1099-105
references.pmid: 18561166
references.citation: Cell Stress Chaperones. 2005 Spring;10(1):7-11
references.pmid: 15832942
references.citation: Toxicol Appl Pharmacol. 2005 May 1;204(3):216-37
references.pmid: 15845415
references.citation: J Neurobiol. 1994 Jan;25(1):23-34
references.pmid: 7906712
references.citation: Ecotoxicol Environ Saf. 2002 Jul;52(3):211-3
references.pmid: 12297081
references.citation: J Drug Target. 2003 Aug;11(7):391-406
references.pmid: 15203928
references.citation: Environ Toxicol Chem. 2007 Jul;26(7):1418-24
references.pmid: 17665681
references.citation: J Exp Biol. 1998 Sep;201(Pt 18):2637-45
references.pmid: 9716515
references.citation: Science. 2010 Jan 8;327(5962):152-3
references.pmid: 20056879
references.citation: Environ Health Perspect. 1997 Aug;105(8):812-8
references.pmid: 9347896
references.citation: PLoS One. 2009 Aug 03;4(8):e6481
references.pmid: 19649264
references.citation: Pest Manag Sci. 2005 Feb;61(2):111-25
references.pmid: 15619715
references.citation: Environ Entomol. 2009 Jun;38(3):514-23
references.pmid: 19508759
references.citation: Toxicol Appl Pharmacol. 1996 Nov;141(1):288-98
references.pmid: 8917702
references.citation: Science. 2007 Oct 12;318(5848):283-7
references.pmid: 17823314
references.citation: Toxicol Lett. 1996 Jun;85(3):127-33
references.pmid: 8644124
references.citation: J Econ Entomol. 2009 Apr;102(2):474-9
references.pmid: 19449624
references.citation: J Vet Pharmacol Ther. 2007 Feb;30(1):25-31
references.pmid: 17217397
references.citation: Nat Rev Cancer. 2002 Jan;2(1):48-58
references.pmid: 11902585
references.citation: J Exp Biol. 2005 Dec;208(Pt 23):4363-76
references.pmid: 16339857
references.citation: Med Vet Entomol. 2008 Mar;22(1):48-54
references.pmid: 18380653
references.citation: Cancer Res. 1981 May;41(5):1967-72
references.pmid: 7214365
references.citation: J Neurosci. 2009 Mar 18;29(11):3538-50
references.pmid: 19295159
references.citation: Antimicrob Agents Chemother. 2011 May;55(5):2224-32
references.pmid: 21300828
references.citation: BMC Genomics. 2009 Apr 21;10:170
references.pmid: 19383151
references.citation: Comp Biochem Physiol B Biochem Mol Biol. 1998 Dec;121(4):443-50
references.pmid: 9972316
references.citation: J Agric Food Chem. 2003 Dec 31;51(27):8005-10
references.pmid: 14690387
references.citation: PLoS One. 2010 Mar 19;5(3):e9754
references.pmid: 20333298