title: Impact of endotoxin on the expression of drug transporters in the placenta of HIV-1 transgenic (HIV-Tg) rats.
abstract: BACKGROUND
  Inflammatory responses in HIV (+) patients may be exacerbated due to reports of subclinical endotoxemia and existing immune dysregulation. As inflammation has been reported to mediate changes in the expression of transporters, this could be potentiated in pregnant HIV (+) women. Similar to humans, the HIV-Tg rat model develops immune dysregulation and chronic AIDS-like conditions. Our objective was to examine the expression of placental drug transporters in HIV-Tg rats in response to low-dose endotoxin.
  
  
  METHODS
  Pregnant HIV-Tg rats or wild-type littermates (WT) were treated with low dose bacterial endotoxin 0.1mg/kg (n=8) or 0.25mg/kg (n=4-6) on GD18 and placentas were harvested 18h later. Placental and hepatic expression of transporters and cytokines were examined using qRT-PCR and Western blotting.
  
  
  RESULTS
  As compared to WT, endotoxin administration increased the hepatic and placental expression of IL-6 and TNF-α to a greater extent in HIV-Tg rats (p<0.05). The placental mRNA and protein expression of Abcb1a and Slco2b1 was significantly decreased in endotoxin-treated HIV-Tg but not WT rats and downregulation of Slco4a1 mRNA was more pronounced in the HIV-Tg group (p<0.05). These changes significantly correlated with the placental expression of pro-inflammatory cytokines. Abcc3 mRNA expression was increased in the placenta of endotoxin treated WT rats only, while placental expression of Abcc1, Abcc2 and Abcc4 was not significantly affected in both WT and HIV rats. Endotoxin imposed a pronounced downregulation in the hepatic expression of Abcb1a, Abcc2, Abcc4, Abcg2, Slco1a1, Slco1b2 and Slc29a1 in both HIV-Tg and WT rats; however, Abcb1b expression was increased in HIV but not WT rats.
  
  
  CONCLUSIONS
  Our results indicate that low-dose endotoxin resulted in an augmented inflammatory response in HIV-Tg rats accompanied with significant changes in the placental expression of several drug transporters. Our data suggests that subclinical endotoxemia and other co-existing infections may alter the placental transfer of drugs in the HIV population.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, ON, Canada.
authors.forename: Ragia H
authors.initials: RH
authors.lastname: Ghoneim
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, ON, Canada.
authors.forename: Dea
authors.initials: D
authors.lastname: Kojovic
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, ON, Canada. Electronic address: m.piquette.miller@utoronto.ca.
authors.forename: Micheline
authors.initials: M
authors.lastname: Piquette-Miller
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015497:HIV-1 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011916:Rats, Inbred F344; D055647:Rats, Transgenic
chemical_list: C000715087:ABCC2 protein, human; D016207:Cytokines; D008070:Lipopolysaccharides; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2
keywords: Drug transport; Endotoxin; Human immunodeficiency virus (HIV); Inflammation; P-glycoprotein; Pregnancy; Transporters