Premium
Involvement of the pregnane X receptor in regulation of transporters during inflammation
Author(s) -
Teng S.,
PiquetteMiller M.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.193
Subject(s) - pregnane x receptor , multidrug resistance associated protein 2 , transporter , cyp3a , medicine , endocrinology , messenger rna , biology , inflammation , receptor , downregulation and upregulation , cyp3a4 , gene expression , gene , nuclear receptor , transcription factor , cytochrome p450 , atp binding cassette transporter , metabolism , genetics
Expression of CYP3A and several drug transporters are down‐regulated during inflammation. On the other hand, activation of the pregnane X receptor (PXR) induces many of these same genes. Hence, the purpose of this study was to elucidate involvement of PXR in the regulation of drug transporters during inflammation. Methods Wild‐type (+/+) and PXR‐null (−/−) mice were injected i.p. for 4 days with 50 mg/kg of the PXR activators PCN or RU486. Another group of (+/+) and (−/−) mice were treated with endotoxin (LPS, 5 mg/kg i.p.) or interleukin‐6 (IL‐6, 10,000 U i.p.) for 6 hours. Levels of CYP3A11, MRP2, MRP3, OATP2, BSEP and PXR mRNA were measured in RNA isolated from liver via RT‐PCR and normalized to 18S rRNA. Results The hepatic mRNA levels of the transporters MRP2, MRP3, OATP2 and BSEP as well as CYP3A11 and PXR were induced (p <0.001) in PCN and RU486 treated (+/+) but not (−/−) mice, confirming involvement of PXR in the induction of these genes. As compared to controls, treatment of (+/+) mice with LPS resulted in a 40‐80% (p<0.05) suppression of mRNA levels of all transporter genes, CYP3A11 and PXR. LPS‐treated (−/−) mice demonstrated similar down‐regulation of OATP2, BSEP and MRP3 however LPS‐mediated changes in MRP2 and CYP3A11 mRNA were significantly different than that seen in (+/+) mice. In IL‐6 treated (+/+) mice, the mRNA levels of each transporter, PXR and CYP3A11 were all suppressed by 40–60% (p<0.05). On the other hand, these genes were not significantly affected by IL‐6 in the (−/−) mice. Conclusions These results suggest that PXR is involved, in part, in the mechanism of transporter and CYP3A11 down‐regulation during inflammation. Clinical Pharmacology & Therapeutics (2004) 75 , P51–P51; doi: 10.1016/j.clpt.2003.11.193