Disease relevance of Fmo1

• Mouse FMO1 and FMO5 were expressed in E. coli and show similar mobility to the native proteins as determined by SDS-PAGE [1].
• Before N-methylthiourea would produce toxicity, it would be further biotransformed to its S-oxidized metabolites mainly by FMO [2].

High impact information on Fmo1

• OBJECTIVES: To date, six flavin-containing monooxygenase (FMO) genes have been identified in humans, FMOs 1, 2, 3, 4 and 6, which are located within a cluster on chromosome 1, and FMO5, which is located outside the cluster [3].
• The objectives were to review and update current knowledge of the structure and expression profiles of these genes and of their mouse counterparts and to determine, via a bioinformatics approach, whether other FMO genes are present in the human and mouse genomes [3].
• Organization and evolution of the flavin-containing monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters [3].
• In addition, we describe a novel human FMO gene cluster on chromosome 1, located 4 Mb telomeric of the original cluster [3].
• RNase protection assays showed that the most abundant isoform in newborn liver, lung, kidney and brain, and in adult lung and kidney is FMO1, but in adult liver FMO5 is present in greatest amounts [4].

Biological context of Fmo1

• 4. Developmentally, FMO1 and FMO5 are expressed in foetuses as early as gestation days 15 and 17 and equally between genders until puberty [5].
• MMI requires metabolic activation by both P450 monooxygenase and flavin-containing monooxygenase (FMO) before it produces the hepatotoxicity [2].

Anatomical context of Fmo1

• Hepatic flavin-containing monooxygenase (FMO) activity of microsomes from adult CD-1, Swiss-Webster, C57BL/6, and DBA/2 mice was found to be significantly higher in females than in males [6].
• FMO1 mRNA is present in neurons of the cerebrum and in the choroid plexus [4].
• The study also provided a systematic quantitative comparison of the steady-state mRNA levels of FMO1 to 5 in several major human organs (i.e., liver, lung, kidney, small intestine, and brain) [7].
• These results suggest that N-methylmercaptoimidazole increases the amount of MPTP delivered from the peripheral to the central nervous system, presumably by inhibiting MPTP N-oxygenation via the hepatic microsomal flavin-containing monooxygenase [8].
• Purification of the flavin-containing monooxygenase from mouse and pig liver microsomes [9].

Associations of Fmo1 with chemical compounds

• In addition, testosterone administration to females (sexually intact and gonadectomized animals) reduced FMO1 expression and obviated FMO3 expression [10].
• Interestingly, FMO1 protein levels were increased in sexually intact males following treatment with 17 beta-estradiol; however, only a slight increase in FMO3 protein level was observed [10].
• The Km value for tamoxifen is 1.2 mM for mouse FMO1 (human FMO1 is not expressed in adults) and 1.4 mM for human FMO3, with no detectable activity being expressed toward tamoxifen by FMO5 from either mouse or human [11].
• Molecular cloning of mouse liver flavin containing monooxygenase (FMO1) cDNA and characterization of the expression product: metabolism of the neurotoxin, 1,2,3,4-tetrahydroisoquinoline (TIQ) [12].
• The expressed FMO1 protein showed activity toward methimazole, and FMO5 was active toward noctylamine [1].

Other interactions of Fmo1

• Protein and mRNA levels appear to be coregulated with regard to gender-selective or gender-specific expression of FMO1 or FMO3, respectively [6].
• In situ hybridization localized FMO1 and 5 mRNAs to the perivenous, and FMO 2, 3 and 4 mRNAs to the periportal, regions of the liver [4].
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective neurotoxin to the nigrostriatal dopaminergic neurons, has been shown to be metabolized by microsomal flavin-containing monooxygenase (FMO) to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide and by cytochrome (cyt.) P-450 to 4-phenyl-1,2,3,6-tetrahydropyridine in the liver [13].
• Polyamine effects on cytochrome P-450- and flavin-containing monooxygenase-mediated oxidation of xenobiotics [14].
• With the procedure described, flavin-containing monooxygenase activity can be accurately measured in whole cell homogenates without interference due to NADPH oxidase activities [15].

Analytical, diagnostic and therapeutic context of Fmo1

• In males, castration dramatically increased FMO3 and FMO1 expression, and testosterone replacement to castrated males resulted in ablation of FMO3 expression [10].
• Role of metabolism by flavin-containing monooxygenase in thioacetamide-induced immunosuppression [16].

References