Abstract
Endotoxin-induced inflammation decreases the hepatic expression of several drug transporters, metabolizing enzymes, and nuclear transcription factors, including pregnane X receptor (PXR). As the nuclear factor κB (NF-κB) is a major mediator of inflammation, and reciprocal repression between NF-κB and PXR signaling has been reported, the objective of this study was to examine whether NF-κB directly regulates the expression of transporters or exerts its effect indirectly via PXR. PXR-deficient (−/−) or wild-type (+/+) male mice were dosed with the selective NF-κB inhibitor PHA408 (40 mg/kg i.p.) or vehicle (n = 5–8/group), followed by endotoxin (5 mg/kg) or saline 30 minutes later. Animals were sacrificed at 6 hours; samples were analyzed using quantitative reverse-transcription polymerase chain reaction and Western blots. Endotoxin induced tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and inducible nitric oxide synthase in PXR (+/+) and (−/−) mice. As compared with saline controls, endotoxin administration imposed 30%–70% significant decreases in the expression of Abcb1a, Abcb11, Abcc2, Abcc3, Abcg2, Slc10a1, Slco2b1, and Slco1a4 in PXR (+/+) and (−/−) mice to a similar extent. Preadministration of PHA408 attenuated endotoxin-mediated changes in both PXR (+/+) and (−/−) mice (P < 0.05). Our findings demonstrate that endotoxin activates NF-κB and imposes a downregulation of numerous ATP-binding cassette and solute carrier transporters through NF-κB in liver and is independent of PXR. Moreover, inhibition of NF-κB attenuates the impact of endotoxin on transporter expression. As NF-κB activation is involved in many acute and chronic disease states, disease-induced changes in transporter function may be an important source of variability in drug response. This information may be useful in predicting potential drug–disease interactions.
Footnotes
- Received June 6, 2017.
- Accepted July 28, 2017.
This work was supported by an operating grant from the Canadian Institutes of Health Research [MOP 13346]. W.A.A. is a recipient of the King Abdul-Aziz University Scholarship for Postgraduate Studies.
This work was previously presented as a poster presentation at the following meeting: 2017 American Society of Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting; 2017 March 15–18; Washington, DC.
There are no conflicts of interest to declare.
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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