S

Since the FMOs and cytochromes P450 are closely associated and can catalyze some of the same reactions, it is important to be able to determine which enzyme is primarily responsible for the formation of a given metabolite. This is of particular importance for in vitro-in vivo correlation and drug interaction studies. Experimentally, the enzymes can be distinguished136 by heat and by running the reactions at higher pH. If the microsomal preparation is heated (45 °C for 5 min) before NADPH is added to initiate the reaction, cytochrome P450 maintains its activity while that of FMO is lost. If in a separate experiment the pH of the incubation mixture is raised to 9, FMO maintains activity but cytochrome P450 activity is virtually abolished, particularly in the presence of a detergent.

5.05.2.2.2 Oxidation at a nitrogen atom

FMO N-hydroxylates both amphetamine (21) and methamphetamine (20), to generate the hydroxylamines 137 and 138, respectively (Scheme 15).162 It then catalyzes a second N-hydroxylation in both metabolites. The two N,N-dihydroxy intermediates eliminate water, to generate the oxime in the case of 139 and the nitrone in the case of 140.

Both FMO3 and extra-hepatic FMO1 have been shown to be effective in oxidizing the nonsteroidal antiinflammatory agent benzydamine (141)163 to benzydamine N-oxide (142), with only a minor contribution from cytochrome P450 (eqn [43]). FMO is also the major catalyst for the conversion of the antipsychotic clozapine (143)164 and the anticancer agent tamoxifen (145),165 and for the cerebral metabolism of the psychoactive drug imipramine (147),166 to their corresponding N-oxides (144, 146, and 148, respectively) (eqns [44]-[46]).

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