Flavin-containing monooxygenases FMOs

The assessment of clearance is complicated by the numerous mechanisms by which compounds may be cleared from the body. These mechanisms include oxidative metabolism, most commonly by CYP enzymes, but also in some cases by other enzymes including but not limited to monoamine oxidases (MAO), flavin-containing monooxygenases (FMO), and aldehyde oxidase [45, 46], Non-oxidative metabolism such as conjugation or hydrolysis may be effected by enzymes such as glucuronyl transferases (UGT), glutathione transferases (GST), amidases, esterases, or ketone reductases, as well as other enzymes [47, 48], In addition to metabolic pathways, parent compound may be excreted directly via passive or active transport processes, most commonly into the urine or bile. 

Monooxygenation of xenobiotics are catalyzed either by the cytochrome P450 (CYP)-dependent monooxygenase system or by flavin-containing monooxygenases (FMO). 

Tertiary amines such as trimethylamine and dimethylamine had long been known to be metabolized to A -oxides by a microsomal amine oxidase that was not dependent on CYP. This enzyme, now known as the microsomal flavin-containing monooxygenase (FMO), is also dependent on NADPH and 02, and has been purified to homogeneity from a number of species. Isolation and characterization of the enzyme from liver and lung samples provided evidence of clearly distinct physicochemical properties and substrate specificities suggesting the presence of at least two different isoforms. Subsequent studies have verified the presence of multiple forms of the enzyme. 

Figure 7.9 Examples of oxidations catalyzed by the flavin-containing monooxygenase (FMO).

In addition to cytochrome P-450 enzymes, another enzyme that mediates phase I oxidations is flavin-containing monooxygenase (FMO), likewise contained in the endoplasmic reticulum. It is especially effective in oxidizing primary, secondary, and tertiary amines. Additionally, it catalyzes oxidation of other nitrogen-containing xenobiotic compounds, as well as those that contain sulfur and phosphorus, but does not bring about hydroxylation of carbon atoms. 

Epoxidation and hydroxylation A-Dealkylation O-Dealkylation -Dealkylation -Oxidation A-Oxidation P-Oxidation Desulfuration Dehalogenation Nitro reduction Azo reduction Cytochrome P450 (CYP) Aflatoxin, aldrin, benzo[a]pyrene, bromobenzene, naphthalene Ethylmorphine, atrazine, dimethylnitrocarbamate, dimethylaniline p-Nitroanisole, chlorfenvinphos, codeine Methylmercaptan Thiobenzamide, phorate, endosulfan, methiocarb, chlorpromazine 2-Acetylaminofluorene Diethylphenylphosphine Parathion, fonofos, carbon disulfide CCLt, CllCb Nitrobenzene O-Aminoazotoluene Flavin-Containing Monooxygenase (FMO)... 

Monooxygenations are those oxidations in which one atom of molecular oxygen is reduced to water while the other is incorporated into the substrate. Microsomal monooxygenation reactions are catalyzed by nonspecific enzymes such as the flavin-containing monooxygenases (FMOs) or the multienzyme system that has cytochrome P450s (CYPs) as the terminal oxidases. 

Figure 6 Stereoselective sulfoxidation of 2-aryl-l,3-oxathiolanes by hog liver flavine-containing monooxygenase (FMO) and cytochrome P450-IIB1. (Taken from Cashman et al 1990.)...

Phase I oxidation generally is described as the addition of an oxygen atom (e.g., as an hydroxyl moiety) to the parent molecule. Phase I oxidation is carried out by multiple enzyme pathways, including the various isoforms of the cytochrome P450 (CYP) family and the non-P450 biotransformation enzymes such as flavin-containing monooxygenase (FMO) and monamine oxidase (MAO). 

Oxidative biotransformations, which constitutes the major portion of Phase I reactions, can be catalyzed by either cytochrome P450s (CYP450) or nonmicrosomal enzymes such as flavin-containing monooxygenases (FMOs), monoamine oxidase (MAOs), alcohol dehydrogenase, and aldehyde dehydrogenase. As listed in Table 5.1,... 

Janmohamed, A., Hernandez, D., Phillips, I.R., Shephand, E.A. (2004). Cell, tissue, sex, and developmental stage-specific expression of mouse flavin-containing monooxygenases (FMOs). Biochemical Pharmacology, 68, 73-83. 

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