Biotransformation of Geldanamycin and 17-Allylamino-17-Demethoxygeldanamycin by Human Liver Microsomes: Reductive versus Oxidative Metabolism and Implications
Comparative metabolite profiling of geldanamycin and 17-allylamino-17-demethoxygeldanamycin (17AAG) using human liver microsomes in normoxia and hypoxia was conducted to understand their differential metabolic fates. Geldanamycin bearing a 17-methoxy group primarily underwent reductive metabolism, g...
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Published in | Drug metabolism and disposition Vol. 35; no. 1; pp. 21 - 29 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.01.2007
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Subjects | |
Online Access | Get full text |
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Summary: | Comparative metabolite profiling of geldanamycin and 17-allylamino-17-demethoxygeldanamycin (17AAG) using human liver microsomes
in normoxia and hypoxia was conducted to understand their differential metabolic fates. Geldanamycin bearing a 17-methoxy
group primarily underwent reductive metabolism, generating the corresponding hydroquinone under both conditions. The formed
hydroquinone resists further metabolism and serves as a reservoir. On exposure to oxygen, this hydroquinone slowly reverts
to geldanamycin. In the presence of glutathione, geldanamycin was rapidly converted to 19-glutathionyl geldanamycin hydroquinone,
suggesting its reactive nature. In contrast, the counterpart (17AAG) preferentially remained as its quinone form, which underwent
extensive oxidative metabolism on both the 17-allylamino sidechain and the ansa ring. Only a small amount (<1%) of 19-glutathione
conjugate of 17AAG was detected in the incubation of 17AAG with glutathione at 37°C for 60 min. To confirm the differential
nature of quinone-hydroquinone conversion between the two compounds, hypoxic incubations with human cytochrome P450 reductase
at 37°C and direct injection analysis were performed. Approximately 89% of hydroquinone, 5% of quinone, and 6% of 17- O -demethylgeldanamycin were observed after 1-min incubation of geldanamycin, whereas about 1% of hydroquinone and 99% of quinone
were found in the 60-min incubation of 17AAG. The results provide direct evidence for understanding the 17-substituent effects
of these benzoquinone ansamycins on their phase I metabolism, reactivity with glutathione, and acute hepatotoxicity. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0090-9556 1521-009X |
DOI: | 10.1124/dmd.106.009639 |