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At least 19 recordsLinked to original sources

PubMed1985

Cytochrome P-450 monooxygenase, epoxide hydrolase and flavin monooxygenase activities in Clara cells and alveolar type II cells isolated from rabbit.

The activities of several enzymes which metabolize xenobiotics were measured and compared in freshly isolated rabbit Clara cells (50-70% purity) and alveolar type II cells (80-95% purity) or microsomal preparations from the isolated cell fractions. The presence of 1 mM nicotinamide in protease and cell isolation buffers increased significantly 7-ethoxycoumarin (7-EC) deethylase and epoxide hydrolase activities in the isolated Clara and type II cells. Isolated Clara cell fractions metabolized 7-EC to umbelliferone at a rate of 241 +/- 27 pmoles/mg prot/min (mean +/- S.E., N =5), while the 7-EC deethylation rate in type II cells was 111 +/- 15 pmoles/mg prot/min. Coumarin hydroxylation activity, however, was more than ten times greater in the Clara cells than in the type II cells on a per mg cellular protein basis. N-oxidation of N,N-dimethylaniline, catalyzed by a flavin monooxygenase, was about 2 times as great in microsomes of Clara cells as in microsomes of type II cells. Epoxide hydrolase activity with benzo(a)pyrene 4,5-oxide as substrate was about 10 times higher in Clara cells than in type II cells. Because of the greater cellular, structural and functional heterogeneity in lung, differential distribution of enzymes responsible for xenobiotic metabolism in this tissue may contribute to cell selective chemical toxicity and carcinogenesis.

Animals↗

PubMed1994

Isolation and structure of a third form of liver microsomal flavin monooxygenase.

Flavin-containing monooxygenases (FMOs) catalyze NADPH-dependent oxygenation of nucleophilic nitrogen, sulfur, and phosphorous atoms in various drugs, pesticides, and xenobiotics. Two forms of this enzyme have been isolated and characterized from rabbit liver microsomes [Ozols, J. (1989) Biochem. Biophys. Res. Commun. 163, 49-55]. The isolation and the structure of a third isoform (FMO3) is presented here. The isolation procedure for FMO3 included solubilization of liver microsomes with cholate, poly(ethylene glycol) precipitation, chromatography on anion- and cation-exchange and hydroxyapatite columns in the presence of nonionic detergents and glycerol. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, FMO3 exhibited a distinct, single band with a M(r) higher than those of FMO1 and FMO2. FMO3 copurified with a polypeptide complex of high FMO activity. This complex consisted of three polypeptides, named FMO3, FMO1a, and FMO2a. The column chromatographic behavior of FMO1 a and 2a was distinct from that of FMO1 and 2. The electrophoretic mobility of FMO1a was identical to that of FMO1. Automated sequence analysis of this polypeptide complex indicated the presence of only one predominant peptide with an open N-terminus. The derived N-terminal amino acid sequence of some 20 residues was identical to the N-terminus of FMO2. The FMO complex, however, did not contain a polypeptide corresponding to the electrophoretic mobility of FMO2. The N-terminus of FMO3 was blocked by an acetyl residue. Automated Edman degradation of peptides obtained from chemical and enzymatic digests established the amino acid sequence of some 514 residues.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMedDate not supplied

Characterization and modulation by drugs of sheep liver microsomal flavin monooxygenase activity.

The flavin monooxygenases (FMO) catalyse the NADPH and oxygen-dependent oxidation of a wide range of nucleophilic nitrogen-, sulfur-, phosphorus-, and selenium heteroatom-containing chemicals, drugs, and agricultural agents. In the present study, sheep liver microsomal FMO activity was determined by measuring the S-oxidation rate of methimazole and the average specific activity obtained from different microsomal preparations was found to be 3.8 +/- 1.5 nmol methimazole oxidized min(-1) mg(-1) microsomal protein (mean +/- SE, n = 7). The presence of 0.1% Triton X-100 in the reaction mixture caused an increase of specific sheep liver microsomal FMO activity towards methimazole to 6.1 +/- 1.4 nmol methimazole oxidized min(-1) mg(-1) microsomal protein (mean +/- SE, n = 6). Metabolism of imipramine and chlorpromazine was measured by following the oxidation of cofactor NADPH spectrophotometrically at 340 nm. Sheep liver microsomal FMO activity towards imipramine and chlorpromazine was found to be 10.7 and 12.3 nmol NADPH oxidized min(-1) mg(-1) microsomal protein, respectively. Characterization of sheep liver enzyme was carried out using methimazole as substrate and the maximum FMO enzyme activity was detected at 37 degrees C and at pH 8.0. The apparent K(m) value of sheep liver microsomal FMO for methimazole was 0.118 mM. Effects of the detergents Triton X-100, Cholate, and Emulgen 913, on FMO activity were determined and FMO activity was found to increase with the addition of detergents to the reaction medium. Sheep liver microsomal FMO-catalysed methimazole oxidation was inhibited by imipramine and chlorpromazine when these drugs were used at high concentrations. Western blot-immunochemical analysis revealed the presence of FMO3 in sheep liver microsomes.

Animals↗

PubMed1974

Oxaziridines as possible intermediates in flavin monooxygenases.

The enzymatic hydroxylation reactions of flavin monooxygenases are suggested to involve an oxaziridine as the active oxygenating agent. The chemistry of these monooxygenases and their nonenzymatic model systems are consistent with an oxaziridine intermediate. Several advantages of the oxaziridine model over the previously proposed "carbonyl oxide" and flavin peroxide models are discussed.

Azirines↗

PubMed2004

The metabolism of pyrazoloacridine (NSC 366140) by cytochromes p450 and flavin monooxygenase in human liver microsomes.

Pyrazoloacridine (PZA) is an experimental antitumor agent presently under investigation for treatment of solid tumors on the basis of its unique mechanism of action and selectivity for human solid tumor xenograft in mice. Using capillary electrophoresis coupled with electrospray ionization mass spectrometry, we have identified three oxidative PZA metabolites, 9-desmethyl-PZA, N-demethyl-PZA, and PZA N-oxide. The cytochrome p450 (CYP) isoforms involved in PZA metabolism were characterized by studies with CYP chemical inhibitors, correlation of marker activities for selected CYPs with formation of the metabolites using a human liver panel, and PZA metabolism by cDNA-expressed CYPs. 9-Desmethyl-PZA formation was catalyzed by CYP1A2, whereas N-demethyl-PZA formation was catalyzed by CYP3A4. PZA N-oxide formation was catalyzed by flavin monooxygenase (FMO) rather than CYP, as determined by studies with chemical inhibitors of FMO and metabolism by cDNA-expressed human flavin monooxygenase. After administration of [10b-(14)C]PZA to mice, six urinary metabolites were detected by high-performance liquid chromatography UV and radiochromatograms including 9-desmethyl-PZA, N-demethyl-PZA, and PZA N-oxide. Trace concentrations of 9-desmethyl-PZA and PZA N-oxide were detected in mouse plasma. PZA N-oxide and N-demethyl-PZA were detected in urine from patients after PZA administration. PZA, 9-desmethyl-PZA, and PZA N-oxide inhibited growth of A375 human melanoma cells. IC(50) values were 0.17, 0.11, and 7.0 micro M, respectively, for the three molecules.

Acridines↗

PubMed2000

Abnormalities of flavin monooxygenase as an etiology for sideroblastic anemia.

We postulated that a deficiency of flavin monooxygenase (FMO)-a ferrireductase component of cells-could produce sideroblastic anemia. FMO is an intracellular ferrireductase which may be responsible for the obligatory reduction of ferric to ferrous iron so that reduced iron can be incorporated into heme by ferrochelatase. Abnormalities of this mechanism could result in accumulation of excess ferric iron in mitochondria of erythroid cells to produce ringed sideroblasts and impair hemoglobin synthesis. To investigate this hypothesis we obtained blood from patients with sideroblastic anemia and normal subjects. Extracts of peripheral blood lymphocytes were used to measure ferrireduction by utilization of NADPH. Lymphoid precursors are reported to accumulate iron in mitochondria similarly to erythroid precursors. Utilization of lymphoid precursors avoided the need for bone marrow aspirations. We studied three patients with sideroblastic anemia. One patient and his asymptomatic daughter had a significant decrease in ferrireductase activity. They also had markedly diminished concentrations of FMO in lymphocyte protein extracts on Western blots. This was accompanied by increased concentration of mobilferrin in the extracts. These results suggest that abnormalities of FMO and mobilferrin may cause sideroblastic anemia and erythropoietic hemochromatosis in some patients.

Aged↗

PubMed1995

Characterization of hepatic flavin monooxygenase from the marine teleost turbot (Scophthalmus maximus L.).

1. The presence and properties of flavin monooxygenase (FMO) in liver of the marine teleost, turbot (Scophthalmus maximus) were examined in relation to organic xenobiotic metabolism and osmoregulation. 2. Hepatic microsomes of sexually mature fish contained NADPH-dependent FMO as evidenced by the conversion of N,N-dimethylaniline (DMA) to DMA-N-oxide, and immunorecognition of single bands (approximate apparent molecular weight of 55 kDa) by antibodies to mammalian FMO 1 and FMO 2. Additionally, Northern analysis using a full-length cDNA probe to mammalian FMO 1 revealed a single hybridizing band of approximately 2.5 kb. 3. No significant differences were seen between male and female turbot FMO with respect to DMA N-oxidase activity, levels of immunoreactive protein (with anti-FMO 1 or anti-FMO 2) and gene expression (hybridizing mRNA). 4. Hepatic microsomal DMA N-oxidase activity was inhibited by methimazole (an FMO substrate) and trimethylamine (TMA), but not by piperonyl butoxide (a P450 inhibitor). Inhibition by TMA is indicative of a role for FMO in osmoregulation, catalysing the conversion of TMA to TMA N-oxide. DMA N-oxidase activity was optimal at pH 8.8 and 25 degrees C, and displayed Michaelis-Menten kinetics with respect to DMA (apparent Km = 88 microM).

Animals↗

PubMedDate not supplied

Effects of genetic or chemically induced diabetes on imipramine metabolism. Respective involvement of flavin monooxygenase and cytochrome P-450-dependent monooxygenases.

Imipramine metabolism has been studied in both type I (streptozotocin-induced insulin-deficient) and type II (genetically insulin-resistant) diabetes in mice. In both types of diabetes, the formation of imipramine N-oxide is increased. In type I diabetes, desmethyl- and 2-hydroxyimipramine are additionally increased. The inhibition of imipramine metabolism by anti-cytochrome P-450 reductase antibodies led to the conclusion that cytochrome P-450-dependent monooxygenases are not involved in the N-oxidation of imipramine. This metabolic route is only supported by the flavin monooxygenase, whose activity is increased by diabetes. The pharmacological implications of altered imipramine metabolism in diabetic states are discussed in relation to the drug metabolism in human diabetes.

Animals↗

PubMed2005

Genetic polymorphisms of flavin monooxygenase 3 in sulindac-induced regression of colorectal adenomas in familial adenomatous polyposis.

Sulindac is a nonsteroidal antiinflammatory drug with a chemopreventive effect in patients with familial adenomatous polyposis (FAP). In vivo, the active form of sulindac is sulindac sulfide, which is inactivated by the hepatic microsomal enzyme, flavin monooxygenase 3 (FMO3). In humans, numerous polymorphisms exist in FMO3, which alter enzymatic activity and subsequent substrate metabolism. We recently showed that certain polymorphic forms of FMO3 with reduced activity were associated with a more favorable response to sulindac in preventing the formation of adenomas in patients with FAP without polyps at baseline. Here, we determined whether these FMO3 polymorphisms correlated with the ability of sulindac to regress polyposis in patients with FAP who had polyps prior to treatment. Nineteen patients were treated with 150 mg sulindac twice a day for 6 months. The size and number of polyps in each patient was assessed at baseline (prior to the administration of sulindac), and at 3 and 6 months. Genotyping was done on seven established FMO3 polymorphisms with functional significance-M66I, E158K, P153L, V257M, E305X, E308G, and R492W. Statistical analyses were done with Wilcoxon rank sum test. Of the loci examined, only E158K and E308G showed polymorphic changes. Six patients exhibited polymorphisms in both E158K and E308G loci and were designated as genotype combination 1. The remaining patients were designated as genotype combination 2. Over the course of treatment, patients with genotype combination 1 had a greater reduction in both the size and number of polyps than those with genotype combination 2. These results suggest that combined polymorphic changes in the E158K and E308G alleles may protect against polyposis in patients with FAP treated with sulindac.

Adenoma↗

PubMed2001

Cytochromes P450 and flavin monooxygenases--targets and sources of nitric oxide.

This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 01 meeting in Orlando, FL. The presentations addressed the mechanisms of inhibition and regulation of cytochrome P450 and flavin monooxygenase enzymes by nitric oxide. They also highlighted the consequences of these effects on metabolism of drugs and volatile amines as well as on important physiological parameters, such as control of blood pressure, renal ion transport, and steroidogenesis. This is achieved via regulation of P450-dependent prostacyclin, hydroxyeicosatetraenoic acid, and epoxyeicosatrienoic acid formation. Conversely, the mechanisms and relative importance of nitric oxide synthases and P450 enzymes in NO production from endogenous and synthetic substrates were also addressed.

Animals↗

PubMed2001

Metabolism of a disulfiram metabolite, S-methyl N,N-diethyldithiocarbamate, by flavin monooxygenase in human renal microsomes.

S-Methyl N,N-diethyldithiocarbamate (MeDDC), a metabolite of the alcohol deterrent disulfiram, is converted to MeDDC sulfine and then S-methyl N,N-diethylthiocarbamate sulfoxide, the proposed active metabolite in vivo. Several isoforms of CYP450 and to a lesser extent flavin monooxygenase (FMO) metabolize MeDDC in the liver. The human kidney contains FMO1 and several isoforms of CYP450, including members of the CYP3A, CYP4A, CYP2B, and CYP4F subfamilies. In this study the metabolism of MeDDC by the human kidney was examined, and the enzymes responsible for this metabolism were determined. MeDDC was incubated with human renal microsomes from five donors or with insect microsomes containing human FMO1, CYP4A11, CYP3A4, CYP3A5, or CYP2B6. MeDDC sulfine was formed at 5 microM MeDDC by renal microsomes at a rate of 210 +/- 50 pmol/min/mg of microsomal protein (mean +/- S.D., n = 5) and by FMO1 at 7.6 +/- 0.2 nmol/min/nmol (n = 3). Oxidation of 5 microM MeDDC was negligible by all CYP450 tested (< or =0.03 nmol/min/nmol). Inhibition of FMO by methimazole or heat diminished MeDDC sulfine formation 75 to 89% in renal microsomes. Inhibition of CYP450 in renal microsomes by N-benzylimidazole or antibody to the CYP450 NADPH reductase had no effect on MeDDC sulfine production. Benzydamine N-oxidation, a probe for FMO activity, correlated with MeDDC sulfine formation in renal microsomes (r = 0.951, p = 0.013). The K(M) values for MeDDC sulfine formation by renal microsomes and recombinant human FMO1 were 11 and 15 microM, respectively. These results demonstrate a role for the kidney and FMO1 in the metabolism of MeDDC in humans.

Chromatography, High Pressure Liquid↗

PubMed2006

Auxin biosynthesis by the YUCCA flavin monooxygenases controls the formation of floral organs and vascular tissues in Arabidopsis.

Auxin biosynthesis in plants has remained obscure although auxin has been known for decades as a key regulator for plant growth and development. Here we define the YUC gene family and show unequivocally that four of the 11 predicted YUC flavin monooxygenases (YUC1, YUC2, YUC4, and YUC6) play essential roles in auxin biosynthesis and plant development. The YUC genes are mainly expressed in meristems, young primordia, vascular tissues, and reproductive organs. Overexpression of each YUC gene leads to auxin overproduction, whereas disruption of a single YUC gene causes no obvious developmental defects. However, yuc1yuc4, yuc2yuc6, all of the triple and quadruple mutants of the four YUC genes, display severe defects in floral patterning, vascular formation, and other developmental processes. Furthermore, inactivation of the YUC genes leads to dramatically reduced expression of the auxin reporter DR5-GUS in tissues where the YUC genes are expressed. Moreover, the developmental defects of yuc1yuc4 and yuc1yuc2yuc6 are rescued by tissue-specific expression of the bacterial auxin biosynthesis gene iaaM, but not by exogenous auxin, demonstrating that spatially and temporally regulated auxin biosynthesis by the YUC genes is essential for the formation of floral organs and vascular tissues.

Arabidopsis↗

PubMed2004

Genetic polymorphisms of human flavin monooxygenase 3 in sulindac-mediated primary chemoprevention of familial adenomatous polyposis.

PURPOSE: Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) effective in regressing adenomas in patients with familial adenomatous polyposis (FAP). However, a recent randomized trial showed that sulindac, when compared with placebo, failed to prevent the development of adenomatous polyps in genotypically positive but phenotypically negative FAP patients. The present study determined whether polymorphisms in the gene encoding flavin monooxygenase 3 (FMO3), a hepatic microsomal enzyme that inactivates sulindac, played a role in determining the efficacy of sulindac in preventing polyposis in this cohort of FAP patients. EXPERIMENTAL DESIGN: Genotyping was performed on seven established FMO3 polymorphisms previously shown to have functional relevance-M66I, P153L, E158K, V257M, E305X, E308G, and R492W-in 21 and 20 FAP patients, who received sulindac and placebo, respectively. RESULTS: None of the 41 patients exhibited heterozygous or homozygous M66I and R492W variant alleles, or homozygous P153L, V257M, and E305X variant alleles. Among sulindac-treated patients who did not develop adenomas ("responders"), 4 (33%) were homozygous for E158K and 2 (17%) were homozygous for E308G variant alleles. In contrast, none of the patients on sulindac who developed adenomas ("nonresponders") exhibited homozygosity for either of the two variant alleles. In addition, polymorphisms in the E158K or E308G allele were associated with a significant reduction in mucosal prostanoid levels in patients treated with sulindac. CONCLUSIONS: Polymorphisms in FMO3, particularly at the E158K and E308G loci, may reduce activity in catabolizing sulindac and result in an increased efficacy to prevent polyposis in FAP.

Adenomatous Polyposis Coli↗

PubMed2005

Interaction of auxin and ERECTA in elaborating Arabidopsis inflorescence architecture revealed by the activation tagging of a new member of the YUCCA family putative flavin monooxygenases.

The aboveground body of higher plants has a modular structure of repeating units, or phytomers. As such, the position, size, and shape of the individual phytomer dictate the plant architecture. The Arabidopsis (Arabidopsis thaliana) ERECTA (ER) gene regulates the inflorescence architecture by affecting elongation of the internode and pedicels, as well as the shape of lateral organs. A large-scale activation-tagging genetic screen was conducted in Arabidopsis to identify novel genes and pathways that interact with the ER locus. A dominant mutant, super1-D, was isolated as a nearly complete suppressor of a partial loss-of-function allele er-103. We found that SUPER1 encodes YUCCA5, a novel member of the YUCCA family of flavin monooxygenases. The activation tagging of YUCCA5 conferred increased levels of free indole acetic acid, increased auxin response, and mild phenotypic characteristics of auxin overproducers, such as elongated hypocotyls, epinastic cotyledons, and narrow leaves. Both genetic and cellular analyses indicate that auxin and the ER pathway regulate cell division and cell expansion in a largely independent but overlapping manner during elaboration of inflorescence architecture.

Amino Acid Sequence↗

PubMedDate not supplied

Effect of cortisol and urea on flavin monooxygenase activity and expression in rainbow trout, Oncorhynchus mykiss.

Expression of flavin-containing monooxygenase(s) (FMO) correlates with salinity exposure in certain species of euryhaline fish, such as the rainbow trout, Oncorhynchus mykiss. The mechanism(s) by which salinity regulates FMO is unclear. Adult rainbow trout were infused through the dorsal aorta with either cortisol or urea. At 500 ng/ml, cortisol caused a significant increase in FMO-catalyzed thiourea oxidase activity in gill and liver microsomes. FMOI expression, however, was significantly increased by the high cortisol dose only in gill microsomes. The levels of TMAO and urea were not altered by cortisol. In the liver, urea infusion caused an increase in hepatic FMO activity. FMO expression and activity correlated with elevated tissue urea levels, but TMAO concentrations were not related. These results indicate that FMO expression and activity may be partially controlled by the osmoregulatory/stress hormone. cortisol, and concentrations of the organic osmolyte, urea, in the rainbow trout.

Animals↗

PubMed1999

Flavin monooxygenase 3 (FMO3) polymorphism in a white population: allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism.

AIM: The flavin-containing monooxygenase 3 (FMO3) has been shown to be genetically polymorphic. In vitro, the enzyme contributes to the N-oxidation of clozapine, caffeine, and several other drugs. We therefore wanted to analyze population frequencies and allelic linkage of FMO3 mutations and their functional effect on the metabolism of clozapine and caffeine. METHODS: This study included 204 patients treated with clozapine for schizophrenia and 192 healthy volunteers receiving a 100 mg oral test dose of caffeine. FMO3 polymorphisms M66I, P153L, E158K, V257M, E305X, E308G, and R492W were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Ratios of serum clozapine N-oxide over clozapine and of urine theobromine versus paraxanthine were used as in vivo indicators of FMO3 activity. RESULTS: From the known FMO3 amino acid variants, only K158 (frequency 0.426), G308 (0.225), and M257 (0.069) were found; mutations I66, L153, X305, and W492 were not found in the 396 subjects. Linkage analysis revealed seven different alleles; the most frequent of these was the wild-type E158-V257-E308 (0.534), followed by K158-V257-G308 (0.199) and K158-V257-E308 (0.192). Subjects with these frequent variants of FMO3, however, did not differ in clozapine N-oxidation or caffeine oxidation compared with the wild-type. CONCLUSION: There are several genetic polymorphisms for the FMO3 enzyme. The effects on the metabolism of caffeine or clozapine could not be shown, indicating that the mutations have only minor functional effects or that substrate affinity is too low to be clinically relevant.

Adult↗

PubMed1984

Hydroperoxyflavin-mediated oxidations of organosulfur compounds. Model studies for the flavin monooxygenase.

Kinetic and product studies were carried out for the reaction of a synthetic hydroperoxyflavin with a series of organosulfur compounds as a model for the flavin-containing monooxygenase of mammalian liver (FMO). S-Oxidized products were identified, and the kinetics of the oxidation reactions were consistent with a mechanism involving attack of a sulfur nucleophile on the terminal oxygen atom of the hydroperoxyflavin. These results provide information about the substrate oxygenation step of FMO not available from steady-state enzyme kinetics.

Animals↗

PubMed2006

Oxidative activation of thiacetazone by the Mycobacterium tuberculosis flavin monooxygenase EtaA and human FMO1 and FMO3.

Thiacetazone (TAZ) and ethionamide (ETA) are, respectively, thiourea- and thioamide-containing second line antitubercular prodrugs for which there is an extensive clinical history of cross-resistance in Mycobacterium tuberculosis. EtaA, a recently identified flavin-containing monooxygenase (FMO), is responsible for the oxidative activation of ETA in M. tuberculosis. We report here that EtaA also oxidizes TAZ and identify a sulfinic acid and a carbodiimide as the isolable metabolites. Both of these metabolites are derived from an initial sulfenic acid intermediate. Oxidation of TAZ by EtaA at basic pH favors formation of the carbodiimide, whereas neutral or acidic conditions favor formation of the sulfinic acid. The same metabolites are formed from TAZ by human FMO1 and FMO3. The sulfenic acid and carbodiimide metabolites, but not the sulfinic acid product, readily react with glutathione, the first to regenerate the parent drug and the second to give a glutathione adduct. These reactions may contribute to the antitubercular activity and/or toxicity of TAZ.

Antitubercular Agents↗