Similar results were reported for ABCC transporter expression in rat choroid plexus. Notably, ABCC1 is localized at the basolateral membrane of choroid plexus, but Gazzin et al described a major differ ence in the localization of ABCB1 and ABCC1 proteins between the blood brain and the blood CSF barrier with strongest expression of ABCC1 at the choroidal sellectchem epithe lium. Indeed, ABCC proteins contribute to the protective role of the choroid plexus and mediate basolateral efflux of conjugates resulting from choroidal drug metabolism into the blood. Although it is known that the choroid plexus is important in regulating the distribution of vari ous pharmacologically active compounds between the blood and the CSF, the characterization of the involved human ABC transporters gives new insights into the func tion of the CSF barrier.
Furthermore, ABCBs and ABCCs are inducible transporters and are highly responsive to chem otherapeutics, carcinogens, inflammation, heat shock, hypoxia Inhibitors,Modulators,Libraries and irradiation. They are regulated by a com plex network of transcriptional cascades, such as by mul tiple ligand activated nuclear receptors like retinoid X receptor, farnesoid X receptor, constitutive androstane receptor and the xenobiotic receptor pregnane X receptor. There is also evidence for the transcription factors AP 1, p53, Egr 1 and WT 1 to participate in their regulation with NF Y, Sp1 and Sp3 being involved in the constitutive expression. Recently, an upregulation of ABCB1, ABCB4 and ABCC4 transcripts was reported in human embryonic kidney cells that conditionally expressed wild type HNF4 .
An important role of HNF4 in the transcriptional control of drug transporters was reported for human hepatocytes as determined by adenoviral HNF4 siRNA mediated knockdown. We also Inhibitors,Modulators,Libraries employed an siRNA mediated functional knockdown of HNF4 and found ABCC1 gene expression to be massively repressed. There is a need to improve an understanding of the mechanism by which transporters are regulated. This will impact the design of novel CNS therapeutics. Targeting transporters may thus be useful in achieving therapeutic tissue levels of CNS drugs. Conclusion We report expression of HNF4 in choroid plexus of the human and rat brain. This factor might regulate expres sion of some ATP binding cassette transporters. Targeting of HNF4 may impact efficacy of pharmacotherapy Inhibitors,Modulators,Libraries of CNS drugs.
Methods Human Inhibitors,Modulators,Libraries and rat tissue A total of n 7 human and n 7 rat tissues were analyzed. Samples of human choroid plexus were kindly provided Inhibitors,Modulators,Libraries by T. Arendt. Paraffin embedded slices of human choroid plexus for immunohistochemistry were kindly provided by C. Grothe. Human liver tissue was obtained from patients undergoing hepatic resections and were kindly provided by selleck chemicals llc J. Klempnauer. Patient characteristics are given in Table 5. Control human brain RNA was purchased from BD Bio sciences. Samples of rat choroid plexus were kindly provided by H. Hilbig and K. Spanel Borowski.