A comparison between stereospecificity of oracin reduction and stereoselectivity of oxidation of 11-dihydrooracin enantiomers in vitro in rat and guinea pig

11-dihydrooracin (DHO) arises from the potential cytostatic drug oracin thr ough the metabolic conversion of its prochiral centre (C-11). The participa tion of reduction enzymes on production of DHO enantiomer under various inc ubation conditions were tested in rat and guinea pig microsomal and cytosol ic fractions. Interesting differences in stereospecificity of oracin reduct ion enzymes were found. Reduction stereospecificity was further studied on rat and guinea pig isolated hepatocytes. The enantiomers were detected in r at and guinea pig hepatocytes in the (+)/(-) ratio 63/37 and 32/68 respecti vely. As the differences in the amounts of DHO enantiomers can be caused no t only by stereospecificity of oracin reduction but also by subsequent conv ersion of the enantiomer, stereoselectivity of DHO oxidation to oracin was investigated. Synthetically prepared pure (+)- and (-)-DHO were incubated w ith rat or guinea pig microsomes and cytosol and with various coenzymes und er aerobic or anaerobic conditions. Significant oxidation of DHO to oracin was observed in rat microsomes. This oxidation depends on NADPH and O-2 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. Chirality 11:510-515, 1999. (C) 1999 Wiley-Liss, Inc.