Monooxygenases flavin-containing

Monoamine oxidases are integral outer mitochondrial membrane proteins that catalyze the oxidative deamination of primary and secondary amines as well as some tertiary amines. MAO occurs as two enzymes, MAO-A and MAO-B, which differ in substrate selectivity and inhibitor sensitivity (Abell and Kwan, 2001 Edmondson et al., 2004 Shih et al., 1999). A number of MAO inhibitors have been developed for clinical use as antidepressants and as neuroprotective drugs. Clinically used drug substances include, among others, moclobemide, a relatively selective reversible MAO-A inhibitor, and L-deprenyl, an irreversible selective inhibitor of MAO-B. In vitro, clorgyline and L-deprenyl are used as selective irreversible inhibitors of MAO-A and B, respectively. (Note For in vitro studies using irreversible inhibitors, preincubation of the irreversible inhibitor with the enzyme prior to initiation of the substrate reaction is required for optimal inhibition.) Expressed MAO-A and MAO-B are not readily available via commercial resources however, MAO-A and MAO-B have been evaluated and are active in subcellular fractions. While monoamine oxidases are located in the mitochondria, many microsomal preparations are contaminated with monoamine oxidases during the preparation of the microsomal subcellular fraction and thus microsomes are sometimes used to evaluate monoamine oxidase activity in combination with selective inhibitors. 

A study comparing monoamine oxidase activity between Japanese and Caucasian livers used rizatriptan as the model substrate (Iwasa et al., 2003). The Japanese livers were evaluated for monoamine oxidase activity using both 

The enzyme responsible for the biotransformation of capecitabine to 5 -deoxy-5-fluorocytidine (a precursor to 5-fluorouracil) was evaluated using purified enzyme, cytosol, and microsomes. The purified CES cytosolic enzyme, inhibited by the carboxylesterase inhibitors bis-nitrophenyphosphate and diisopropylfluorophosphate, was identified as belonging to the subgroup CES lAl based on the result of the N-terminal amino acid sequence. 

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Kim YM, Ziegler DM. Size limits of thiocarbamides accepted as substrates by human flavin-containing monooxygenase 1. Drug Metab Dispos 2000 28 1003-6. 

Schlenk D, DR Buhler (1991) Role of flavin-containing monooxygenase in the in vitro biotransformation of aldicarb in rainbow trout (Oncorhyncus mykiss). Xenobiotica 21 1583-1589. 

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. 

SGAs = second-generation antipsychotics (SGAs) FM03 = flavin-containing monooxygenase TCAs = tricyclic antidepressants Adapted from de Leon et al., 2005b... 

Cashman, J. R. etal. (2001). Population distribution ofhuman flavin-containing monooxygenase form 3 gene polymorphisms. Drug Metab. Dispos., 29, 1629-37. 

Itagaki, K., Carver, G.T. andPhilpot, R.M. (1996) Expression and characterization ofa modified flavin-containing monooxygenase 4 from humans. The Journal of Biological Chemistry, 271, 2012—20107. 

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-... 

Cashman JR, Zhang J. Interindividual differences of human flavin-containing monooxygenase 3 genetic polymorphisms and functional variation. Drug Metab Dispos 2002 30(10) 1043-1052. 

Ziegler DM. Recent studies on the structure and function of multisubstrate flavin-containing monooxygenases. Annu Rev Pharmacol Toxicol 1993 33 179-199. 

Cashman JR, Xiong YN, Xu L, et al. N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3) role in bioactivation and detoxication. J Pharmacol Exp Ther 1999 288(3) 1251—1260. 

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. 

Rettie, A., Bogucki, B., Lim, I. and Meier, P. (1990). Steroselective sulfadioxidation of a series of alkyl P-tolyl sulfides hy microsomal and purified flavin-containing monooxygenases. Mol. Pharmacol. 37 643-651. 

Poulsen LL. 1981. Organic sulfur substrates for the microsomal flavin-containing monooxygenase. Rev Biochem Toxicol 3 33-49. 

Tynes RE, Hodgson E. 1985. Magnitude of involvement of the mammalian flavin-containing monooxygenase in the microsomal oxidation of pesticides. J Agric Food Chem 33 471-479. 

Tam TW, Liu R, Amason IT et al (2009) Actions of ethnobotanicaUy selected Cree antidiabetic plants on human cytochrome P450 isoforms and flavin-containing monooxygenase 3. 1 Ethnopharmacol 126 119-126... 

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

The following is review on the molecular and physical properties of this class of monooxygenases, which are also known as hydroxylases. A typical monooxygenase reaction is the hydroxylation of an alkane to an alcohol which involves a reduced cosubstrate that reduces a second atom within the O2 molecule to form water. Flavin-containing monooxygenases include lysine oxygenase and 4-hydroxybenzoate hydroxylase. Reduced pteri-dines are involved in the phenylalanine hydroxylase and tryptophan hydroxylase reactions. See also Cytochrome P-450... 

Using pig and human microsomes and cDNA-expressed human flavin-containing monooxygenase, Lin and Cashman demonstrated a metabolic detoxification pathway that converts tyramine into the HA derivative, 20, and the anti oxime, 21, which was sufficiently stable to permit its chemical characterization". ... 

Biochemical transformations of the —C=N—OH function of synthetic drugs to an NO and to nitroso intermediates " were recently demonstrated as a new pathway for metabolic activation of oxime-containing molecules. These reactions were recently explored in detail, and may underlie possible biochemical transformations of the —C=N— OH moiety in mammalian tissues, which are likely to be catalyzed by cytochrome P450 and by flavin-containing monooxygenase " . 

Tugnait, M., Hawes, E.M., McKay, G., Rettie, A.E., Haining, R.L., and Midha, K.K. (1997) N-oxygenation of clozapine by flavin-containing monooxygenase. Drug Metab Dispos 25 524-527. 

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