RT Journal Article
SR Electronic
T1 Liver Receptor Homolog-1 Regulates Organic Anion Transporter 2 and Docetaxel Pharmacokinetics
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 980
OP 988
DO 10.1124/dmd.118.080895
VO 46
IS 7
A1 Fangjun Yu
A1 Tianpeng Zhang
A1 Lianxia Guo
A1 Baojian Wu
YR 2018
UL http://dmd.aspetjournals.org/content/46/7/980.abstract
AB 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-1hep−/− 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-1fl/fl) and Lrh-1hep−/− 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-1hep−/− 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-1hep−/− mice due to reduced hepatic uptake. In conclusion, Lrh-1 transcriptionally regulates Oat2, thereby impacting tissue uptake and pharmacokinetics of Oat2 substrates.