Disease relevance of Fmo1

• These results suggest that NO acts directly in a cGMP-independent mechanism by decreasing the half-life of FMO1 mRNA, thereby inducing impairment of FMO-related functions in endotoxemia [1].
• This study demonstrates alteration of FMO- and CYP-mediated drug metabolism in vitro by dietary I3C or DIM and suggests the potential for altered toxicity of tamoxifen and nicotine in vivo [2].
• Methimazole is a compound administered to humans for the treatment of hyperthyroidism and is used experimentally as a model substrate for the flavin-containing monooxygenase (FMO) system [3].

High impact information on Fmo1

• Flavin-containing monooxygenase alternate substrates, N,N-dimethylaniline, n-octylamine, and methimazole inhibited the S-oxidase activities [4].
• The levels of another microsomal enzyme, flavin-containing monooxygenase, were also measured and found to be regulated by testosterone, but the ontogenic profiles and the effects of gonadectomy and hormone replacement indicated clear differences in its regulation when compared to the other male-specific enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)[5]
• In contrast to these NO-mediated in vivo suppressive effects on the mRNA and enzyme contents of FMO1 as well as the FMO activity, the NO generated in vitro from sodium nitroprusside did not inhibit the FMO activities present in microsomes of rat and rabbit liver as well as those present in rabbit kidney and lung [6].
• Attendant with the reduction of plasma nitrite/nitrate concentration by single and repeated doses of NOS inhibitors, activity and content of FMO1 in liver microsomes isolated from these NOS inhibitor cotreated rats were restored partially (in single-dose inhibitors) or completely (in repeat doses) [6].
• When this overproduction of NO in the LPS-treated rats was inhibited in vivo by a single or repeat doses of either a general NOS inhibitor N(G)-nitro-L-arginine or a specific iNOS inhibitor aminoguanidine, the FMO1 mRNA levels were not severely depressed (70-85% of the control level) [6].

Biological context of Fmo1

• Furthermore, spermine-NONOate, but not the cGMP analog, 8-bromo-cGMP, dose- and time-dependently attenuated FMO1 mRNA stability in actinomycin-D-pretreated cells, resulting in decreases in protein levels and biochemical activity [1].
• An expression plasmid, pAMFMO, was constructed and the FMO protein expressed in yeast (AH22) [7].
• The S-oxidation activities of thiobenzamide and thiourea were enhanced by n-octylamine, a known enhancer of FMO, and inhibited by alpha-naphthylthiourea, a known inhibitor of FMO [7].
• The dog FMO1 amino acid sequence is 88, 86, and 89% identical to sequences of human, rabbit, and pig FMO1, respectively [8].
• Hormonal regulation of microsomal flavin-containing monooxygenase: tissue-dependent expression and substrate specificity [9].

Anatomical context of Fmo1

• Western blots of OM and liver revealed no change in FMO1 protein; however, FMO2, 3, and 5 decreased in olfactory microsomes with age [10].
• Microsomal flavin-containing monooxygenase activity in rat corpus striatum [11].
• Hormonal regulation of microsomal flavin-containing monooxygenase activity by sex steroids and growth hormone in co-cultured adult male rat hepatocytes [12].
• Both S-conjugates 1 and 2 were cytotoxic in LLC-PK1 cells and in isolated rat renal proximal tubular cells, and the cytotoxicity of sulfide 1, but not of S-oxide 2, in isolated renal proximal tubular cells was reduced in presence of methimazole, an inhibitor of the flavin-containing monooxygenase [13].
• To investigate the hormonal control of the expression of flavin-containing monooxygenase (FMO; EC 1.14.13.8) under defined in vitro conditions, adult male rat hepatocytes were isolated by collagenase perfusion and co-cultured with rat liver epithelial cells of primitive biliary origin [12].

Associations of Fmo1 with chemical compounds

• Flavin-containing monooxygenase activity in hepatocytes and microsomes: in vitro characterization and in vivo scaling of benzydamine clearance [14].
• Because cDNA-expressed rabbit FMO3 and FMO1 were previously shown to preferentially catalyze methionine and S-benzyl-L-cysteine (SBC) sulfoxidations, respectively, these substrates were used to isolate two distinct S-oxidase activities from the same rat liver microsomal preparation [15].
• To examine a molecular basis for the influence of total parenteral nutrition +/- choline on monooxygenase regulation, hepatic microsomal activity of the FMO and CYP2E1 was examined [16].
• Although the data did not reach statistical significance, selective immunoblot studies using hepatic microsomes from rats treated with total parenteral nutrition + choline showed that compared with controls, FMO1 protein was decreased 1.4-fold and FMO3 increased 1.3-fold, respectively [16].
• The N-oxygenation of trimethylamine was used as an in vivo selective functional marker for FMO [16].

Other interactions of Fmo1

• Inversely, the expression of FMO1 in the female rat kidneys does not seem to be modified as a function of age while the expression of FMO3 is strongly increased [17].
• Superoxide dismutase, catalase and methional proved capable of inhibiting the microsomal oxidation of thiobenzamide, which is most probably catalyzed by the flavin-containing monooxygenase [18].
• Further, addition of methimazole, a high affinity substrate for the flavin-containing monooxygenase, reduced the residual mutagenicity in the systems containing antibody to P-450d and cytochrome P-450 reductase to 9% and 19%, respectively, of the appropriate control values [19].
• Sensitive and specific chromatographic assays for the measurement of flavin-containing monooxygenase (N-oxygenase and S-oxygenase activities) and aldehyde oxidase activities in rat hepatocyte primary cultures were developed [20].
• Our laboratory has previously shown that dietary administration of indole-3-carbinol (I3C) to male Fischer 344 rats has the very unusual property of inducing hepatic levels of a number of cytochrome P450s (CYPs), especially CYP1A1, while markedly inhibiting the levels of flavin-containing monooxygenase (FMO) 1 protein and its catalytic activity [2].

Analytical, diagnostic and therapeutic context of Fmo1

• Castration also reduced flavin-containing monooxygenase-dependent activities, but not to the same extent as hypophysectomy [9].
• Microsomal content of FMO1 (the major form in rat liver) in LPS-treated rats as determined by immunoblotting, was severely decreased as well [6].
• The ability of the recombinant yeast to produce R(+)-flosequinan from flosequinan sulfide could be maintained for at least 2 days and exemplifies the value of a recombinant yeast expressing FMO as a stereoselective bioreactor [21].
• The purified FMO was resolved by SDS-PAGE into two bands (approximately 57 and 61 KDa, respectively) both of which cross-reacted with antibody to rabbit pulmonary FMO [22].
• An assay system of flavin-containing monooxygenase was developed by fluorometric determination of benzydamine (BZY) N-oxidation with HPLC [23].

References