[BIOTRANSFORMATION OF GELDANAMYCIN AND 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN BY HUMAN LIVER MICROSOMES: REDUCTIVE VERSUS OXIDATIVE METABOLISM AND IMPLICATIONS]
>>Drug Metab Dispos. 2006 Sep 29; [Epub ahead of print]
BIOTRANSFORMATION OF GELDANAMYCIN AND 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN BY HUMAN LIVER MICROSOMES: REDUCTIVE VERSUS OXIDATIVE METABOLISM AND IMPLICATIONS.
Lang W, Caldwell GW, Li J, Leo GC, Jones WJ, Masucci JA.
Johnson & Johnson Pharmaceutical Research & Development, LLC.
Comparative metabolite profiling of geldanamycin and 17-allylamino-17-demethoxygeldanamycin (17AAG) using human liver microsomes in normoxia and hypoxia was conducted in order 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. Upon 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 degrees 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 degrees 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.<<
Rick, you may have left this building, but I thought you might be able to translate or elucidate the implications for us laymen. This one's a bit beyond me.
Cheers, Tuck |
