| Abstrakt: |
Only in the presence of NADPH and oxygen digitoxosides of digitoxigenin can be metabolized by rat liver microsomes. The metabolism includes 12β-hydroxylation, formation of digitoxosides less the terminal digitoxose and of lipophilic metabolites. The lipophilic metabolites of digitoxin (dt-3), digitoxigeninbis-digitoxoside (dt-2), and of - mono-digitoxoside (dt-1) are formed by oxidation of the axial OH-group of the terminal digitoxosyl yielding the corresponding dehydro-digitoxosides. The structure could be confirmed by comparison with the synthetic compounds 15′-dehydro-dt-3, 9′-dehydro-dt-2, and 3′-dehydro-dt-1, respectively. The terminal dehydro-digitoxosyl can be split off by liver microsomes even in the absence of NADPH. However, no further cleavage of the resulting digitoxosides could be detected. A cleavage rate of 2.8 nmoles/mg microsomal protein × 30 min was observed for both 15′-dehydro-dt-3 and 9′-dehydro-dt-2 (substrate concentration 50 μM). In contrast to that, only 0.4 nmole 3′-dehydro-dt-1 was cleaved under equal conditions. For the cleavage of 15′-dehydro-dt-3 an apparent K of 200 μM and a V of 440 pmoles dt-2 formed per mg microsomal protein x min was measured. Our results indicate that not the native but only the dehydro-digitoxosides can be cleaved. Therefore, two successive monoxygenase catalysed oxidations are necessary for the cleavage of the sugar chain of dt-3 before dt-1, the main substrate of conjugation enzymes, can be formed. Moreover, digitoxigenin will not be formed because of the high stability of 3′-dehydro-dt-1. [ABSTRACT FROM AUTHOR] |
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