Effects of inducers and inhibitors of rat liver mono-oxygenases on digitoxin metabolism

In rats, microsomal mono-oxygenases are involved in the cleavage and hydroxylation of digitoxin (dt-3).2 Previous to hydrolytic cleavage the terminal digitoxosyl has to be oxidized to the corresponding dehydro-digitoxosyl. The microsomal formation rate of 15'-dehydro-dt-3 could be enhanced 3 to 7 fold by pretreatment with pregnenolone-16α-carbonitril, spironolactone, cancrenoate and cyproterone. Phenobarbital and polychlorinated biphenyls had no effect, whereas polyaromatic hydrocarbons caused a significant decrease of both C12-β-hydroxylation and sugar oxidation. The inducing effects of the steroids were less pronounced in the formation of 9'-dehydro-dt-2 and 3'-dehydro-dt-1. For the latter, phenobarbital evoked an inducing effect by factor 1.7. The sugar chain oxidation could be inhibited by metyrapone, spironolactone, cancrenoate and digitoxigenin when added in vitro. a-Naphthoflavone was a weak inhibitor only. The results indicate that the terminal digitoxosyl oxidation is due to a specific isocytochrome P450 (or pattern of isocytochromes) inducible by some synthetic steroids.