Paavo Honkakoski's Research group
We study the basic biology of closely related nuclear receptors (NRs) CAR and PXR which regulate many drug-metabolizing enzymes such as CYP3A4 and CYP2B6 and drug transporters such as ABCB1 and ABCC2. Thus, these drug-responsive NRs contribute to the clearance and metabolism-dependent toxicity of xenobiotics (Figure). They also modulate expression of genes involved in glucose and lipid metabolism, linking them to energy homeostasis and diabetes, obesity and dyslipidemias. An intriguing feature of CAR and PXR is their very diverse species differences in the profiles of activating chemicals, which complicates any predictions from animal studies to the human situation.
We have highlighted the complexity and overlap of CAR and PXR signalling at the DNA and mRNA levels. We developed the first QSAR models and molecular dynamics simulations for both mouse and human CAR. We devised and validated robust assays for to detect NR activators, and identified by mutagenesis key CAR residues that contribute to ligand recognition, selectivity and receptor activation. We also have generated for pharmaceutical research several hepatic and intestinal cell lines that display improved capacity for drug metabolism.
Figure 1. Exposure to drugs and other xenobiotics activates nuclear receptors, which in turn enhance the capacity for drug metabolism and transport in the hepatic and intestinal cells. This may have a profound effect on other drugs’ elimination and toxicity.
Key scientists and research areas
Paavo Honkakoski, PhD, Professor in Biopharmacy: Current research activities revolve around basic biology and applications of drug-responsive nuclear receptors (NRs) such as CAR and PXR. NRs are key transcription factors controlling inducible expression of drug-metabolizing enzymes and drug transporters. We study the mechanisms of action, ligand specificities and target genes of NRs, and use NRs as switches to develop cell lines with improved capacity for drug metabolism. Our studies have been funded by the Academy of Finland, the Finnish Funding Agency for Innovation TEKES, Centre for International Mobility CIMO and University of Eastern Finland.
Paavo Honkakoski (paavo.honkakoski(at)uef.fi), tel +358403552490