Monooxygenated metabolites

Figure 5.49 (a) Total-ion-current trace, and (b) the reconstructed ion chromatogram of mjz 510.2 0.5 (monooxygenated metabolites) from LC-MS analysis of human microsomal incubation of Glyburide. Reprinted with permission from Zhang, H., Henion, J., Yang, Y. and Spooner, N., Anal. Chem., 72, 3342-3348 (2000). Copyright (2000) American Chemical Society. 

The degradation of acenaphthene is initiated by benzylic monooxygenation, and the pathway was determined using [l- C]acenaphthene by the isolation of intermediate metabolites (Selifonov et al. 1998). Importantly, the method proved applicable even when only limited biotransformation of the substrates had taken place by partial oxidation. 

Epoxides, also known to chemists as oxiranes, result from the monooxygenation of a C=C bond in olefins or aromatic rings. Such reactions of monooxygenation to produce epoxides as metabolites or metabolic intermediates... 

Reduced flavins, unlike reduced nicotinamides, are reactive towards molecular oxygen, and an intermediate produced in this reaction is a more potent oxygenating agent than molecular oxygen is itself. A number of enzymes have evolved which utilize this intermediate to oxygenate certain metabolites. These reactions usually entail monooxygenation (Scheme 5). There are, however, at least two examples of dioxygenation that have been reported... 

LC-MS and LC-MS/MS methods combined with HDX experiments were able to unambiguously differentiate structures of four monooxygenated isomeric analogs of DL. Importantly, HDX is required to differentiate between hydroxylamine and iV-oxide derivatives. This method can provide critical information for identification of novel metabolites. 

Cytochrome P450 enzymes use molecular oxygen to create ROS that monooxygenate many natural and xenobiotic species. With natural species and some foreign chemicals, the oxygenation is helpful, producing metabolites that are eliminated from the body. With others, however, such as aromatic hydrocarbons, the ROS metabolites are far more toxic than the parent compounds and create OS. Aerobic life is dependent upon the formation and deactivation of ROS. OS arises when ROS are formed at a rate that exceeds the rate of deactivation. 

FIGURE 9.7 Fragmentation of compound B and its two isomeric monooxygenated metabolites, B1 and B2. 

For example, the non-nucleoside reverse transcriptase inhibitor capravirine, an antiviral compound originally developed for the treatment of HIV, undergoes multiple oxidations in human body. Numerous monooxygenated as well as di-, tri-, and tetra-oxygenated metabolites are formed [40]. Using a sequential incubation ... 

Yu W, Powell WS. Analysis of leukotrienes, lipoxins, and monooxygenated metabolites of arachidonic acid by reversed-phase high-pressure liquid chromatography. Anal Biochem 1995 226 241-251. 

---