Involvement of Nuclear Factor κB, not Pregnane X Receptor, in Inflammation-Mediated Regulation of Hepatic Transporters

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 kappa B (NF-kappa B) is a major mediator of inflammation, and reciprocal repression between NF-kappa B and PXR signaling has been reported, the objective of this study was to examine whether NF-kappa B directly regulates the expression of transporters or exerts its effect indirectly via PXR. PXR-deficient (-/-) orwild-type (+/+) malemice were dosed with the selective NF-kappa B 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-a, interleukin (IL)-6, IL-1 beta, 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-kappa B and imposes a downregulation of numerous ATP-binding cassette and solute carrier transporters through NF-kappa B in liver and is independent of PXR. Moreover, inhibition of NF-kappa B attenuates the impact of endotoxin on transporter expression. As NF-kappa B 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.