Molecular and Biochemical Pharmacology

Group leader:

Moshe Finel, Ph.D., Docent

 

MBP group members

Division of Pharmacology and Toxicology at the Faculty »»

Description

The research in Molecular and Biochemical Pharmacology group is mainly centered on the metabolism of xenobiotics, including drugs, and endogenous compounds by conjugation with glucuronic acid. Such glucuronidation reactions are catalyzed by an array of UDP-glucuronosyltransferases (UGTs) and we are interested in these processes from the point of view of both the enzyme and the aglycone substrate. We have cloned all the 19 human UGTs of subfamilies UGT1A, UGT2A and UGT2B and we are expressing them using baculovirus-infected insect cells. The recombinant proteins are used for multiple studies on the structure, function and substrate specificity of individual UGTs. Additional lines of research that are linked to glucuronidation include enzyme-assisted synthesis of glucuronide metabolites, develop of specific UGT inhibitors, drug metabolism within Caco-2 cells, and development of screening methods for the interactions of UGTs with different chemical libraries.

We are also interested and have been involved in non-UGTs research projects, like Protein Kinase C and Catechol O-methyltransferase (COMT), and currently consider other directions.

The study of recombinant UGTs is also at the basis of several productive scientific collaborations with different laboratories, both in Finland and abroad.

Selected publications

  • Kurkela M, Garcia-Horsman JA, Luukkanen L, Mörsky S, Taskinen J, Baumann M, Kostiainen R, Hirvonen J, and Finel M (2003) Expression and characterization of recombinant human UDP-glucuronosyltransferases (UGTs); UGT1A9 is more resistant to detergent inhibition than the other UGTs, and was purified as an active dimeric enzyme. J Biol Chem 278:3536–3544.
  • Kurkela M, Mörsky S, Kostiainen R, Hirvonen J, and Finel M (2004) An active and water-soluble truncation mutant of the human UDP-glucuronosyltransferase 1A9. Mol Pharmacol 65:826-831.
  • Alonen A, Aitio O, Hakala K, Luukkanen L, Finel M, and Kostiainen R (2005) Biosynthesis of dobutamine monoglucuronides and glucuronidation of dobutamine by recombinant human UDP-glucuronosyltransferases. Drug Metab. Dispos 33:657-663.
  • Finel M, Li X, Gardner-Stephen D, Bratton S, Mackenzie PI, and Radominska-Pandya A (2005) Human UDP-glucuronosyltransferase 1A5: identification, expression and activity. J Pharmacol Exper Ther 315:1143-1149.
  • Sten T, Qvisen S, Uutela P, Luukkanen L, Kostiainen R, Finel M (2006) Prominent but reverse stereoselectivity in propranolol glucuronidation by human UDP-glucuronosyltransferases 1A9 and 1A10. Drug Metab Dispos 34:1488-14894.
  • Kurkela M, Patana A-S, Mackenzie PI, Court MH, Tate CG, Hirvonen J, Goldman A, and Finel M (2007) Interactions with other human UDP-glucuronosyltransferases (UGTs) attenuate the consequences of the Y485D mutation on the activity and substrate affinity of UGT1A6. Pharmacogenet Genomics 17:115-126.
  • Bichlmaier I, Kurkela M, Joshi T, Siiskonen A, Rüffer T, Lang H, Suchanová B, Vahermo M, Finel M, and Yli-Kauhaluoma J (2007) Isoform-selective Inhibition of the Human UDP-glucuronosyltransferase 2B7 by Tricyclic Isolongifo lol Derivatives. J Med Chem 50:2655-2664.
  • Kaivosaari S, Toivonen P, Hesse LM, Koskinen M, Court MH, and Finel M (2007) Nicotine glucuronidation and the human UDP-glucuronosyltransferase UGT2B10. Mol Pharmacol 72:761-768.
  • Patana AS, Kurkela MJ, Goldman A, Finel M (2007) The human UDP-Glucuronosyltransferase - identification of key residues within the nucleotide-sugar binding site. Mol Pharmacol 72:604-611.
  • Finel M, Kurkela M (2008) The UDP-Glucuronosyltransferases as Oligomeric Enzymes. Curr Drug Metabol 9:70-76.
  • Patana AS, Kurkela M, Finel M, Goldman A (2008) Mutation analysis in UGT1A9 suggests a relationship between substrate and catalytic residues in UDP-glucuronosyltransferases. Protein Eng Des Sel 21: 537-543.
  • Alonen A., Finel M., Koistinen R (2008 ) The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan. Biochem Pharmacol 76:763-772.
  • Siissalo S, Zhang H, Stilgenbauer E, Kaukonen AM, Hirvonen J, Finel M (2008) The expression of most UDP-glucuronosyltransferases (UGTs) is increased significantly during Caco-2 cell differentiation, while UGT1A6 is highly expressed also in undifferentiated cells . Drug Metab Dispos 36 : 2331-2336 .
  • Itäaho K, Mackenzie P, Ikushiro SI, Miners J, Finel M (2008) The configuration of the 17-hydroxy group variably influences the glucuronidation of {beta}-estradiol and epiestradiol by human UDP-glucuronosyltransferases. Drug Metab Dispos 36 : 2307-2315 .
  • Sten T, Bichlmaier I, Kuuranne T, Leinonen A, Yli-Kauhaluoma J, Finel M (2009) UGT2B7 and UGT2B17 display converse specificity in testosterone and epitestosterone glucuronidation, whereas UGT2A1 conjugates both androgens similarly. Drug Metab Dispos 37:417-423.
  • Itäaho K, Court M, Uutela P, Kostiainen R, Radominska-Pandya A, Finel M (2009) Dopamine is a low affinity and high specificity substrate for the human UDP-glucuronosyltransferase 1A10. Drug Metab Dispos in press.
  • Sten T, Kurkela MJ, Kuuranne T, Leinonen AT, Finel M (2009) UDP-Glucuronosyltransferases in Conjugation of 5a- and 5b-Androstane Steroids. Drug Metab Dispos 37:2221–2227.
  • Sneitz N, Court MH, Zhang X, Laajanen K, Yee KK, Dalton P, Ding X, and Finel M (2009) Human UDP-glucuronosyltransferase UGT2A2: cDNA construction, expression, and functional characterization in comparison with UGT2A1 and UGT2A. Pharmacogenet Genomics 19:923-934.
  • Sneitz N, Bakker CT, de Knegt RJ, Finel M, and Bosma PJ (2010) Crigler-Najjar syndrome in the Netherlands; Identification of Four Novel Alleles, Genotype-Phenotype Correlation and Functional Analysis of 10 Missense Mutants. Hum Mutat 31:52-59.
  • Manevski N, Kurkela M, Höglund C, Mauriala T, Court MH, Yli-Kauhaluoma J, and Finel M (2010) Glucuronidation of Psilocin and 4-Hydroxyindole by the Human UDP-glucuronosyltransferases. Drug Metab Dispos in press.