Regulation of Hepatic Drug Transporters Expression in Mice During Acute Inflammation

Inflammation generated by many disease conditions is known to alter the expression and activity of several hepatic ABC and SLC transporters and drug-metabolizing enzymes. These pronounced changes in hepatic transporters contribute to altered drug disposition; therefore, understanding the molecular mechanisms would aid in identifying potential sources of drug variability in diseases associated with inflammation. Pregnane X receptor (PXR) and nuclear factor-κB (NF-κB) are regarded as key transcriptional factors that are modulated in response to endotoxin and cytokine signaling. This work assesses the role of NF-κB and PXR in the transcriptional regulation of hepatic transporters and elucidate the signaling pathways behind changes in transporter expression. We hypothesized that the regulatory mechanism of hepatic transporter expression following inflammatory stimuli would depend primarily on the NF-κB signaling pathway and that PXR might play a role in this regulation. Inflammation was induced by either endotoxin or proinflammatory cytokine interleukin (IL)-6 administration in wild type PXR (+/+) and knockout PXR (-/-) mice. The mRNA expression of most transporters was downregulated to a similar extent for PXR (+/+) and PXR (-/-) mice following endotoxin administration. NF-κB inhibition attenuated the impact of endotoxin on transporter expression, suggesting that NF-κB is the major signaling pathway involved in endotoxin-mediated downregulation of hepatic transporter, and it appears to act independent of PXR. Conversely, IL-6-mediated downregulation of Abcb11, Abcc2, Slco2b1 and Slc10a1 was seen in PXR (+/+) but not PXR (-/-) mice, suggesting PXR-dependent regulation. Our IL-6 studies demonstrated that STAT3 inhibition attenuated IL-6-mediated downregulation of almost all transporters. However, IL-6-mediated activation of STAT3 stimulated the release of secondary cytokines that further activated NF-κB. Interestingly, NF-κB target genes (IL-6 and IL-1β) showed (35%-100%) higher basal expression in PXR (-/-) versus PXR (+/+) mice, and NF-κB inhibition attenuated IL-6-mediated changes of transporters in PXR (+/+) mice. Since NF-κB inhibition following IL-6 administration demonstrates indirect involvement of NF-κB in transporter expression via secondary cytokines, findings from these studies indicate that NF-κB is an essential regulator of hepatic transporter expression under inflammatory conditions. Thus, targeting NF-κB in diseases associated with inflammatory conditions could provide a strategy for therapeutic intervention.

Department dc:contributor.department

Pharmaceutical Sciences

Year dc:date.issued

2019

Author dc:creator

• Abualsunun, Walaa Ali

Advisor dc:contributor.advisor

• Piquette-Miller, Micheline

• drug transporters
• Inflammation
• Liver
• signaling pathways

Handle dc:identifier.uri

http://hdl.handle.net/1807/102558

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/102558