Reduction of the potential anticancer drug oracin in the rat liver in-vitro

Studies on the metabolism of the potential cytostatic drug oracin have show n that a principal metabolite of oracin is 11-dihydrooracin (DHO). We condu cted in-vitro experiments to investigate the extent of oracin carbonyl redu ction in microsomal or cytosolic fractions and to find out the enzymes invo lved under these conditions. Among several inducers of rat cytochrome P450 only 3-methylcholanthrene cau sed a significant (P < 0.01) stimulation (1.9 times) of DHO production in m icrosomal fraction and the specific P4501A inhibitor alpha-naphthoflavone s ignificantly (P < 0.01) decreased (twice) the induced reduction activity. C ytochrome P4501A participates in oracin reduction in microsomes. 18 beta-Gl ycyrrhetinic acid, a specific inhibitor of hydroxysteroid dehydrogenase, si gnificantly (P < 0.01) inhibited the production of DHO in the microsomal fr action (>95% inhibition) in comparison with the non-inhibited reaction. Sta tistically significant (P < 0.01) inhibition (95%) of DHO formation was cau sed by metyrapone, which is also the substrate of 11 beta-hydroxysteroid de hydrogenase. The main microsomal enzyme which catalyses the carbonyl reduction of oracin is probably 11 beta-hydroxysteroid dehydrogenase. Important oracin reducti on to DHO in the cytosolic fraction was found. According to its specific se nsitivity towards quercitrin (inhibition by 99%, P < 0.01), the enzyme resp onsible for DHO formation in the rat liver cytosol is postulated to be carb onyl reductase.