title: Reduction of the potential anticancer drug oracin in the rat liver in-vitro.
abstract: Studies on the metabolism of the potential cytostatic drug oracin have shown that a principal metabolite of oracin is 11-dihydrooracin (DHO). We conducted in-vitro experiments to investigate the extent of oracin carbonyl reduction in microsomal or cytosolic fractions and to find out the enzymes involved under these conditions. Among several inducers of rat cytochrome P450 only 3-methylcholanthrene caused a significant (P < 0.01) stimulation (1.9 times) of DHO production in microsomal fraction and the specific P4501A inhibitor alpha-naphthoflavone significantly (P < 0.01) decreased (twice) the induced reduction activity. Cytochrome P4501A participates in oracin reduction in microsomes. 18beta-Glycyrrhetinic acid, a specific inhibitor of hydroxysteroid dehydrogenase, significantly (P < 0.01) inhibited the production of DHO in the microsomal fraction (>95% inhibition) in comparison with the non-inhibited reaction. Statistically significant (P < 0.01) inhibition (95%) of DHO formation was caused by metyrapone, which is also the substrate of 11-hydroxysteroid dehydrogenase. The main microsomal enzyme which catalyses the carbonyl reduction of oracin is probably 11beta-hydroxysteroid dehydrogenase. Important oracin reduction to DHO in the cytosolic fraction was found. According to its specific sensitivity towards quercitrin (inhibition by 99%, P < 0.01), the enzyme responsible for DHO formation in the rat liver cytosol is postulated to be carbonyl reductase.
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic.
authors.forename: B
authors.initials: B
authors.lastname: Szotáková
authors.forename: L
authors.initials: L
authors.lastname: Skálová
authors.forename: V
authors.initials: V
authors.lastname: Wsól
authors.forename: E
authors.initials: E
authors.lastname: Kvasniècková
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004983:Ethanolamines / Q000378:metabolism*; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007546:Isoquinolines / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D004983:Ethanolamines; D007546:Isoquinolines; C103439:oracine; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1