title: Endotoxin-Mediated Downregulation of Hepatic Drug Transporters in HIV-1 Transgenic Rats.
abstract: Altered expression of drug transporters and metabolic enzymes is known to occur in infection-induced inflammation. We hypothesize that in human immunodeficiency virus (HIV)-infected individuals, further alteration could occur as a result of augmented inflammation. The HIV-1 transgenic (Tg) rat is used to simulate HIV pathologies associated with the presence of HIV viral proteins. Therefore, the objective of this study was to examine the effect of endotoxin administration on the gene expression of drug transporters in the liver of HIV-Tg rats. Male and female HIV-Tg and wild-type (WT) littermates were injected with 5 mg/kg endotoxin or saline (n= 7-9/group). Eighteen hours later, rats were euthanized and tissues were collected. Quantitative real-time polymerase chain reaction and Western blot analysis were used to measure hepatic gene and protein expression, respectively, and enzyme-linked immunosorbent assay was used to measure serum cytokine levels. Although an augmented inflammatory response was seen in HIV-Tg rats, similar endotoxin- mediated downregulation of Abcb1a, Abcc2, Abcg2, Abcb11, Slco1a1, Slco1a2, Slco1b2, Slc10a1, Slc22a1, Cyp3a2, and Cyp3a9 gene expression was seen in the HIV-Tg and WT groups. A significantly greater endotoxin- mediated downregulation of Ent1/Slc29a1 was seen in female HIV-Tg rats. Basal expression of inflammatory mediators was not altered in the HIV-Tg rat; likewise, the basal expression of most transporters was not significantly different between HIV-Tg and WT rats. Our findings suggest that hepatobiliary clearances of endogenous and exogenous substrates are altered in the HIV-Tg rat after endotoxin exposure. This is of particular importance because HIV-infected individuals frequently present with bacterial or viral infections, which are a potential source for drug-disease interactions.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ragia H
authors.initials: RH
authors.lastname: Ghoneim
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada m.piquette.miller@utoronto.ca.
authors.forename: Micheline
authors.initials: M
authors.lastname: Piquette-Miller
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004731:Endotoxins / Q000009:adverse effects*; D005260:Female; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000821:virology; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic
chemical_list: C000715087:ABCC2 protein, human; D016207:Cytokines; D004731:Endotoxins; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations