Abstract
Endotoxin-induced inflammation decreases the hepatic expression of several drug transporters, metabolizing enzymes and nuclear transcription factors including PXR. As the nuclear factor 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 ip) 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 qRT-PCR and western blots. Endotoxin induced TNF-α, IL-6 IL-1β and iNOS in PXR (+/+) and (−/−) mice. As compared to 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. Pre-administration 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 ABC and SLC 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.
- cytochrome P450
- efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
- gene regulation/transcription
- inflammation
- liver/hepatic
- nuclear receptors
- pregnane X receptor/PXR/SXR
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics