English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Organic anion transporter 2 (OAT2/SLC22A7) is an uptake transporter that plays an important role in drug disposition. Here, we investigate a potential role of liver receptor homolog-1 (Lrh-1) in regulation of Oat2 and docetaxel pharmacokinetics. Hepatoma cells (Hepa1-6 and HepG2 cells) were transfected with Lrh-1/LRH-1 expression vector or siRNA. The relative mRNA and protein levels of Oat2/OAT2 in the cells or livers of Lrh-1 hep-/- mice were determined by qPCR and Western blotting, respectively. Transcriptional regulation of Oat2/OAT2 by Lrh-1/LRH-1 was investigated using luciferase reporter, mobility shift, and chromatin immunoprecipitation (ChIP) assays. Pharmacokinetic studies were performed with wild-type (Lrh-1 fl/fl ) and Lrh-1 hep-/- mice after intraperitoneal injection of docetaxel. Overexpression of Lrh-1 in Hepa1-6 cells led to significant increases in Oat2 mRNA and protein. Consistently, Lrh-1 knockdown caused decreases in Oat2 mRNA and protein, as well as reduced cellular uptake of PGE2, a prototypical substrate of Oat2. Similarly, an activation effect of LRH-1 on OAT2 expression was observed in HepG2 cells. In addition, the levels of Oat2 mRNA and protein were markedly reduced in Lrh-1 hep-/- mice. Lrh-1/LRH-1 induced the transcription of Oat2/OAT2 in luciferase reporter assays. Truncation analysis revealed a potential Lrh-1 response element (-716- to -702-bp) in Oat2 promoter. Direct binding of Lrh-1 to this response element was confirmed by mobility shift and ChIP assays. Furthermore, systemic exposure of docetaxel was upregulated in Lrh-1 hep-/- mice due to reduced hepatic uptake. In conclusion, Lrh-1 transcriptionally regulates Oat2, thereby impacting tissue uptake and pharmacokinetics of Oat2 substrates.

Liver Receptor Homolog-1 Regulates Organic Anion Transporter 2 and Docetaxel Pharmacokinetics