| First Author | Ning M | Year | 2015 |
| Journal | Biochem Pharmacol | Volume | 94 |
| Issue | 1 | Pages | 46-52 |
| PubMed ID | 25598084 | Mgi Jnum | J:345375 |
| Mgi Id | MGI:6880276 | Doi | 10.1016/j.bcp.2015.01.001 |
| Citation | Ning M, et al. (2015) Hepatocyte nuclear factor (HNF) 4alpha transactivation of cytochrome P450 (Cyp) 2d40 promoter is enhanced during pregnancy in mice. Biochem Pharmacol 94(1):46-52 |
| abstractText | We have recently reported that transactivation of cytochrome P450 (CYP) 2D6 promoter by hepatocyte nuclear factor (HNF) 4alpha is enhanced during pregnancy, and this is triggered in part by altered expression of small heterodimer partner (SHP) and Kruppel-like factor 9 (KLF9). The objective of this study is to determine whether this is conserved for mouse endogenous Cyp2d gene(s). Among the eight Cyp2d homologs of mouse we examined, only Cyp2d40 expression was found induced (by 6-fold) at term pregnancy as compared to pre-pregnancy level. In mice where hepatic Hnf4alpha was knocked-down, the pregnancy-mediated increase in Cyp2d40 expression was abrogated. Results from transient transfection, promoter reporter assays, and electrophoretic mobility shift assays indicated that HNF4alpha transactivates Cyp2d40 promoter via direct binding to -117/-105 of the gene. Chromatin immunoprecipitation assay showed a 2.3-fold increase in HNF4alpha recruitment to Cyp2d40 promoter during pregnancy. Results from mice treated with an SHP inducer (i.e., GW4064) and HepG2 cells co-transfected with KLF9 suggest that neither SHP nor KLF9 is involved in the increased HNF4alpha transactivation of Cyp2d40 promoter during pregnancy. Together, our results indicate that while the underlying molecular mechanism is different from that for CYP2D6, Cyp2d40 is induced during pregnancy through enhanced transactivation by HNF4alpha. |
