title: A comparison between stereospecificity of oracin reduction and stereoselectivity of oxidation of 11-dihydrooracin enantiomers in vitro in rat and guinea pig.
abstract: 11-dihydrooracin (DHO) arises from the potential cytostatic drug oracin through the metabolic conversion of its prochiral centre (C11). The participation of reduction enzymes on production of DHO enantiomer under various incubation conditions were tested in rat and guinea pig microsomal and cytosolic fractions. Interesting differences in stereospecificity of oracin reduction enzymes were found. Reduction stereospecificity was further studied on rat and guinea pig isolated hepatocytes. The enantiomers were detected in rat and guinea pig hepatocytes in the (+)/(-) ratio 63/37 and 32/68 respectively. As the differences in the amounts of DHO enantiomers can be caused not only by stereospecificity of oracin reduction but also by subsequent conversion of the enantiomer, stereoselectivity of DHO oxidation to oracin was investigated. Synthetically prepared pure (+)- and (-)-DHO were incubated with rat or guinea pig microsomes and cytosol and with various coenzymes under aerobic or anaerobic conditions. Significant oxidation of DHO to oracin was observed in rat microsomes. This oxidation depends on NADPH and O2 and is stereoselective for (+)-DHO. The formation of oracin in the guinea pig was greater in cytosol than microsomes, but no significant preference for a particular DHO enantiomer was found.
authors.affiliation: Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic. skaloval@faf.cuni.cz
authors.forename: L
authors.initials: L
authors.lastname: Skálová
authors.forename: V
authors.initials: V
authors.lastname: Wsól
authors.forename: B
authors.initials: B
authors.lastname: Szotáková
authors.forename: E
authors.initials: E
authors.lastname: Kvasnicková
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism; D004983:Ethanolamines / Q000737:chemistry / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D004983:Ethanolamines; D007546:Isoquinolines; C103439:oracine; D000429:Alcohol Oxidoreductases; C119935:oracin reductase