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Research ArticleArticle

Endotoxin-Mediated Downregulation of Hepatic Drug Transporters in HIV-1 Transgenic Rats

Ragia H. Ghoneim and Micheline Piquette-Miller
Drug Metabolism and Disposition May 2016, 44 (5) 709-719; DOI: https://doi.org/10.1124/dmd.115.067827
Ragia H. Ghoneim
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
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Micheline Piquette-Miller
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
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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.

Footnotes

    • Received October 15, 2015.
    • Accepted March 8, 2016.
  • This research was supported by the Canadian Institutes of Health Research [Operating Grant MOP 13346]. R.G. was a recipient of the King Abdulaziz University Scholarship for Postgraduate Studies.

  • This work was previously presented as a poster at the 24th Annual Canadian Conference on HIV/AIDS Research (CAHR-2015); 2015 Apr 30–May 3; Toronto, ON, Canada.

  • dx.doi.org/10.1124/dmd.115.067827.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (5)
Drug Metabolism and Disposition
Vol. 44, Issue 5
1 May 2016
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Research ArticleArticle

Effect of Endotoxin on Drug Transporters in HIV-Tg Rats

Ragia H. Ghoneim and Micheline Piquette-Miller
Drug Metabolism and Disposition May 1, 2016, 44 (5) 709-719; DOI: https://doi.org/10.1124/dmd.115.067827

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Research ArticleArticle

Effect of Endotoxin on Drug Transporters in HIV-Tg Rats

Ragia H. Ghoneim and Micheline Piquette-Miller
Drug Metabolism and Disposition May 1, 2016, 44 (5) 709-719; DOI: https://doi.org/10.1124/dmd.115.067827
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