Dehydro-digitoxosides of digitoxigenin: Formation and importance for the digitoxin metabolism in the rat |
| |
Authors: | A Schmoldt C Rohloff |
| |
Institution: | (1) Pharmakologisches Institut der Universität, Martinistrasse 52, D-2000 Hamburg 20, Federal Republic of Germany |
| |
Abstract: | Summary Only in the presence of NADPH and oxygen digitoxosides of digitoxigenin can be metabolized by rat liver microsomes. The metabolism includes 12 -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 M). 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
m of 200 M and a V
max 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. |
| |
Keywords: | Digitoxin Dehydro-digitoxosides Digitoxoside cleavage Liver microsomes Monoxygenases |
本文献已被 SpringerLink 等数据库收录! |
|