title: The novel anticancer drug oracin: different stereospecificity and cooperativity for carbonyl reduction by purified human liver 11beta-hydroxysteroid dehydrogenase type 1.
abstract: Inherent or acquired resistance of tumor cells to anti-cancer drugs is a problem of major importance in chemotherapy. In addition to detailed research into the mechanisms of drug inactivation, attention has also been paid to the synthesis of new structures. Oracin is a promising cytostatic drug, which is presently in phase II of clinical trials. This investigation was designed to characterize the metabolic inactivation of oracin by carbonyl reduction to 11-dihydrooracin (DHO). We identified 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) as the principal enzyme being responsible for oracin carbonyl reduction in human liver microsomes. The purified 11beta-HSD 1 catalyses this reaction in a stereospecific manner. Formation of (-)-DHO surpasses that of (+)-DHO by a factor of around four. Moreover, 11beta-HSD 1 exhibits enzyme cooperativity for the formation of both enantiomers (Hill coefficients of 2.26 +/- 0.20 and 1.84 +/- 0.29 for (-)-DHO and (+)-DHO, respectively). Comparing the differences in the stereospecificity and Hill coefficients between the microsomes and purified 11beta-HSD 1 could anticipate contribution of another microsomal enzyme. In case of oracin, this enzyme cooperativity may become important with respect to maximal plasma concentrations, and, by inhibition of 11beta-HSD 1, to enhance the chemotherapeutic efficacy of this anti-cancer drug.
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, CZ-50005 Hradec Králové, Czech Republic.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Wsól
authors.forename: Barbora
authors.initials: B
authors.lastname: Szotáková
authors.forename: Lenka
authors.initials: L
authors.lastname: Skálová
authors.forename: Edmund
authors.initials: E
authors.lastname: Maser
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001711:Biotransformation; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D019008:Drug Resistance, Neoplasm; D004983:Ethanolamines / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D004983:Ethanolamines; D007546:Isoquinolines; C103439:oracine; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1