Monooxygenases flavin-containing enzymes

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. 

Cocaine-mediated hepatotoxicity has been associated with the conversion of cocaine to norcocaine and further oxidation products. The enzymes involved in in vitro hepatic oxidative N-demethylation of cocaine (192) were investigated (237), and two different enzymatic pathways appear to be important in the formation of the hepatotoxic metabolite. Cytochrome P-450 monooxygenases accomplish the direct N-demethylation of cocaine to norcocaine (194) as confirmed by induction and inhibition studies (Scheme 42). The second pathway for cocaine N-demethylation involves formation of cocaine /V-oxide (193) as an intermediate and two enzymes. A flavin-containing monooxygenase is first thought to convert cocaine to cocaine /V-oxide, followed by cytochrome P-450-... 

Hamman MA, Haehner-Daniels BD, Wrighton SA, et al. Stereoselective sulfoxidation of sulin-dac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes. Biochem Pharmacol 2000 60(1) 7-17. 

This enzyme [EC 1.14.13.8], also referred to as microsomal flavin-containing monooxygenase and dimethyl-... 

It is highly protein bound (approx. 96%), metabolised in the liver by N-oxidation to inactive metabolites by the enzyme flavin-containing monooxygenase. It is excreted mainly by the kidneys in the form of metabolites and as unchanged drug. 

Ziegler DM (1990) Flavin-containing monooxygenases enzymes adapted for multisubstrate specificity. Trends Pharmacol Sci 11 321-324... 

Microsomal flavin-containing monooxygenases. As well as the cytochromes P-450 MFO system, there is also a system, which uses FAD. This flavin-containing monooxygenase or FMO enzyme system is found particularly in the microsomal fraction of the liver, and the monomer has a molecular weight of around 65,000. Each monomer has one molecule of FAD associated with it. The enzyme may accept electrons from either NADPH or NADH although the former is the preferred cofactor. It also requires molecular oxygen, and the overall reaction is as written for cytochromes P-450 ... 

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. 

Toxicants may also be detoxified by xenobiotic-metabolizing enzymes such as cytochrome P450 or the flavin-containing monooxygenase. It should be borne in mind, however, that these enzymes may also activate toxicants to more reactive, and potentially more toxic, metabolites. 

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. 

MIRANDA, C.L., CHUNG, W., REED, R.E., ZHAO, X., HENDERSON, M.C., WANG, J.L., WILLIAMS, D.E., BUHLER, D.R., Flavin-containing monooxygenase A major detoxifying enzyme for the pyrrolizidine alkaloid senecionine in guinea pig tissues. Biochem. Biophys. Res. Commun., 1991,178, 546-552. 

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. 

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