Differential regulation of human hepatic flavin containing monooxygenase 3 (FMO3) by CCAAT/enhancer-binding protein β (C/EBPβ) liver inhibitory and liver activating proteins

Klick, David E.; Shadley, Jeff D.; Hines, Ronald N.

doi:10.1016/j.bcp.2008.05.002

Cited by 23 publications

(17 citation statements)

References 31 publications

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“…However, recently, in the promoter region of the human FMO3 gene, Klick and coworkers [48] have found a regulatory element that binds C/EBPβ liver-activating protein.…”

Section: Discussionmentioning

confidence: 98%

“…Particularly, the data from Klick and coworkers [48] have demonstrated that CCAAT/enhancer-binding protein β (C/EBPβ) plays a relevant role in the regulation of the expression of the FMO3 gene in humans, as mutation in the region containing the CCAAT binding site strongly reduces the expression of the FMO3 gene. Nevertheless, the mechanism by which steroid could regulate FMO3 accumulation has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 98%

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Regulation of flavin-containing mono-oxygenase (Fmo3) gene expression by steroids in mice and humans

Esposito

Varriale

D’Angelo³

et al. 2014

Hormone Molecular Biology and Clinical Investigation

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Flavin-containing mono-oxygenases (FMOs) are a family of microsomal chemical- and drug-metabolizing enzymes. FMO3 is a major FMO form in adult mouse and human liver. FMO3 mutations have been associated with the incidence and severity of trimethylaminuria (TMAU), a metabolic disorder characterized by the inability of the affected individual to metabolize the odorous trimethylamine to its non-odorous N-oxide. In addition to this primary genetic form, there are other forms of TMAU that support the hypothesis that FMO3 activity may be modulated by steroid hormones. To understand the molecular mechanism involved in the regulation of Fmo3 gene expression by steroid hormones, we performed this study in an in vitro cellular system, mouse liver cells, and on the human FMO3 gene. Dexamethasone, 5α-dihydrotestosterone, thyroid hormone, and progesterone had no effect on the accumulation of Fmo3 mRNA. The use of increased concentration of theophylline inhibited estrogen receptor α (ERα)-mediated transcription of Fmo3 mRNA. 17β-Estradiol inhibited Fmo3 mRNA accumulation. The use of ICI 164,384 abolished the inhibitory effect induced by estrogen. Gel-shift analyses showed a binding in the 5' region of the Fmo3 gene. This binding was abrogated by an excess of a cDNA containing an estrogen-responsive element. An estrogen-binding site was also present in the first intron of the human gene, as demonstrated by the gel-shift assay. Supershift experiments confirmed the binding of ERα in both mouse and human samples. Furthermore, chromatin immunoprecipitation assay confirmed the binding of ERα in the promoter region of mouse Fmo3 and in the first intron of the human FMO3 gene. Thus, 17β-estradiol plays a fundamental role in the regulation of Fmo3 gene transcription.

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“…However, recently, in the promoter region of the human FMO3 gene, Klick and coworkers [48] have found a regulatory element that binds C/EBPβ liver-activating protein.…”

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

Regulation of flavin-containing mono-oxygenase (Fmo3) gene expression by steroids in mice and humans

Esposito

Varriale

D’Angelo³

et al. 2014

Hormone Molecular Biology and Clinical Investigation

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“…1-4). Very recently Klick et al (2008) showed that structural differences in responsive elements in the promoter region can account for some differences among mammalian species in hepatic constitutive FMO3 expression. Although structural differences in aryl hydrocarbon response elements potentially could explain the fact that that FMO3 mRNA levels are highly up-regulated by TCDD in mouse but not in rat, our analysis of AHREs in the two species indicates that the difference in FMO inducibility cannot be explained solely by differences in regulatory motifs between their FMO3 genes (Supplemental Figs.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor-Dependent Induction of Flavin-Containing Monooxygenase mRNAs in Mouse Liver

Celius¹,

Roblin²,

Harper³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Flavin-containing monooxygenases (FMOs) are important in detoxication but generally are considered not to be inducible by xenobiotics. Our recent microarray studies revealed induction of FMO2 and FMO3 mRNAs by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in liver of mice with wild-type aryl hydrocarbon receptor (AHR) but not in Ahr-null mice. The aim of the present study was to delineate mechanisms of FMO regulation. In adult male mice, basal FMO3 mRNA is low but was induced 6-fold at 4 h and 6000-fold at 24 h. The ED50 was approximately 1 g/kg for FMO2 and FMO3, similar to that for the classic AHR-regulated gene, Cyp1a1. In adult female mice basal FMO3 mRNA is high and was not induced at 4 h but was elevated 8-fold at 24 h. FMO5 mRNA was significantly downregulated by TCDD in both male and female adult mice. Juvenile mice show no sex difference in response to TCDD; FMO3 was induced 4 to 6-fold by TCDD in both sexes. Chromatin immunoprecipitation demonstrated recruitment of AHR and aryl hydrocarbon nuclear translocator proteins to Fmo3 regulatory regions, suggesting that induction by TCDD is a primary AHR-mediated event. Although FMO2 and FMO3 mRNAs were highly induced by TCDD in adult males, overall FMO catalytic activity increased only modestly. In contrast to the striking up-regulation of FMO2 and FMO3 in mouse liver, TCDD has little effect on FMO mRNA in rat liver. However, FMO2 and FMO3 mRNAs were highly induced in transgenic mice that express wild-type rat AHR, indicating that lack of induction in rat is not due to an incompetent AHR in this species.

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“…Several factors that regulate FMO transcription are known (33)(34)(35)(36)(37). Estrogen (29) and insulin (34) activate FMO transcription, whereas testosterone (29) and glucagon (37) are repressors of FMO transcription, but FMO5 is again an exception (38).…”

Section: Genomic Organization and Expressionmentioning

confidence: 99%

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

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Edited by F. Peter GuengerichFlavin-containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well-conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes.

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Differential regulation of human hepatic flavin containing monooxygenase 3 (FMO3) by CCAAT/enhancer-binding protein β (C/EBPβ) liver inhibitory and liver activating proteins

Cited by 23 publications

References 31 publications

Regulation of flavin-containing mono-oxygenase (Fmo3) gene expression by steroids in mice and humans

Regulation of flavin-containing mono-oxygenase (Fmo3) gene expression by steroids in mice and humans

Aryl Hydrocarbon Receptor-Dependent Induction of Flavin-Containing Monooxygenase mRNAs in Mouse Liver

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

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