Genetic Variability at the Human FMO1 Locus: Significance of a Basal Promoter Yin Yang 1 Element Polymorphism (FMO1*6)

Department of Pharmacology and Toxicology , Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 10/2003; 306(3):1210-8. DOI: 10.1124/jpet.103.053686
Source: PubMed


The flavin-containing monooxygenases (FMOs) are important for the disposition of a variety of toxicants, therapeutics, and dietary components. Although FMO1 is the dominant isoform in fetal liver and adult kidney and intestine and despite up to a 10-fold intersubject variation in expression, a paucity of information is available on FMO1 genetic variability. To address this issue, 24 samples from the Coriell DNA Polymorphism Discovery Resource Panel were sequenced revealing 10 common single nucleotide polymorphisms (SNPs): four located upstream of the structural gene; three within exonic sequences; one within the intron 1 splice donor site; and two with the 3'-untranslated region. Six of these variants are novel. Compared with other FMO loci within the chromosome 1q23-25 cluster, FMO1 seems more highly conserved. Of the identified FMO1 SNPs, only a C>A transversion 9536 base pairs upstream of the exon 2 ATG start codon (g.-9536C>A) would likely affect function, because it lies within the conserved core binding sequence for the yin yang 1 (YY1) transcription factor. Electrophoretic mobility shift assays demonstrated that the g.-9536C>A transversion eliminated YY1 binding. Furthermore, data from transient expression assays in HepG2 cells suggested this SNP could account for a 2- to 3-fold loss of FMO1 promoter activity. Genotype analysis revealed a g.-9,536A allele (FMO1*6) frequency of 13 and 11% in African- and northern European-Americans, respectively, but a significantly higher frequency of 30% in Hispanic-Americans. Thus, the FMO1*6 variant may account for some of the observed interindividual variation in FMO1 expression.

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Available from: Ronald Hines, Sep 13, 2015
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    • "rs1051740 337T>C Y113H influenced [43] .54 FMO1 rs12720462 1q23-q25 (-)69C>A 5'-UTR influenced [44] .38 NQO1 rs1800566 16q22.1 559C>T P187S influenced [45] .16 "
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    ABSTRACT: Objective: Obstructive respiratory diseases, mainly the chronic obstructive pulmonary disease (COPD) and asthma, are associated with functional polymorphisms of xenobiotic-metabolizing enzymes (XMEs). To date, association for obstructive bronchitis has not been described. Material/methods: In this study, we investigated the genotypes from 26 functional polymorphisms of 20 XMEs in children (n, 1028) at the age of 6 years from the German prospective birth cohort study (LISAplus) and analyzed the associations between genotypes and obstructive bronchitis. Results: For the first time, we found noteworthy gene-disease associations for the functional PON1 M55L and EPHX1 H139R polymorphisms and gene-environment associations for the functional COMT V158M and NQO1 P187S polymorphisms after stratification for maternal active smoking behaviour during pregnancy. The noteworthy associations were substantiated by the biological findings that all the risk genotypes belong to genes involved in oxidative stress and code for proteins with a fast enzymatic activity or concomitantly appear in common estrogene-metabolizing pathway (COMT, NQO1). Conclusion: The oxidative stress has to be taken into account in mechanism of the obstructive bronchitis in early childhood. The risk genotypes may serve as risk factors for respiratory obstruction rather than for signs of COPD or asthma.
    Metabolism: clinical and experimental 06/2012; 61(12). DOI:10.1016/j.metabol.2012.05.013 · 3.89 Impact Factor
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    • "Both neutralize AChE inhibitors: PON1 hydrolyzes selected OPs, notably chlorpyrifos and diazinon (Furlong 2007), and BuChE sequesters all OP and carbamate insecticides (Cokuğraş 2003). In vitro studies suggest that FMO1 –9536A materially reduces promoter activity (Hines et al. 2003). Its product, flavin-containing monooxygenase 1 (FMO1), oxidizes the thioether sulfur of some OP and carbamate insecticides (Hajjar and Hodgson 1980), and for some substrates (e.g., fenthion; Furnes and Schlenk 2004) the resulting sulfoxide is a weaker AChE inhibitor than is its parent compound. "
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    ABSTRACT: Insecticides that target the nervous system may play a role in the development of childhood brain tumors (CBTs). Constitutive genetic variation affects metabolism of these chemicals. We analyzed population-based case-control data to examine whether CBT is associated with the functional genetic polymorphisms PON1C-108T, PON1Q192R, PON1L55M, BCHEA539T, FMO1C-9536A, FMO3E158K, ALDH3A1S134A, and GSTT1 (null). DNA was obtained from newborn screening archives for 201 cases and 285 controls, <or= 10 years of age, and born in California or Washington State between 1978 and 1990. Conception-to-diagnosis home insecticide treatment history was ascertained by interview. We observed no biologically plausible main effects for any of the metabolic polymorphisms with CBT risk. However, we observed strong interactions between genotype and insecticide exposure during childhood. Among exposed children, CBT risk increased per PON1-108T allele [odds ratio (OR) = 1.8; 95% confidence interval (CI), 1.1-3.0] and FMO1-9536A (*6) allele (OR = 2.7; 95% CI, 1.2-5.9), whereas among children never exposed, CBT risk was not increased (PON1: OR = 0.7; 95% CI, 0.5-1.0, interaction p = 0.005; FMO1: OR = 1.0; 95% CI, 0.6-1.6, interaction p = 0.009). We observed a similar but statistically nonsignificant interaction between childhood exposure and BCHEA539T (interaction p = 0.08). These interactions were present among both Hispanic and non-Hispanic white children. Based on known effects of these variants, these results suggest that exposure in childhood to organophosphorus and perhaps to carbamate insecticides in combination with a reduced ability to detoxify them may be associated with CBT. Confirmation in other studies is required.
    Environmental Health Perspectives 01/2010; 118(1):144-9. DOI:10.1289/ehp.0901226 · 7.98 Impact Factor
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    • "Several transcription factors, including CCAAT/enhancer-binding protein-␣ and -␤ and hepatic nuclear factor (HNF)-1␣ and HNF-3, have been shown to play an essential function in sepsis-associated decreases in the transcription of a number of hepatic genes in mice and have been suggested to have similar roles in other inflammatory states (Haaxma et al., 2003). HNF-1␣ and HNF-4␣, among several transcription factors, have been suggested to be involved in FMO1 and FMO3 regulation in humans (Luo and Hines, 2001; Hines et al., 2003; Klick and Hines, 2007). Comparison of human FMO3 promoter elements with other mammalian species revealed striking differences (Klick et al., 2008). "
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    ABSTRACT: The objective of the study was to investigate the regulation of hepatic flavin-containing monooxygenases (Fmo) Fmo1, Fmo3, Fmo4, and Fmo5 in three different mouse models of inflammation, including treatment with Citrobacter rodentium, lipopolysaccharide (LPS), and dextran sulfate sodium (DSS). Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate the steady-state mRNA levels for the various Fmo isoforms in these mouse models of inflammation during different treatment time courses. Fmo3 mRNA was most significantly down-regulated in C. rodentium-treated female mice. Fmo1, Fmo3, and Fmo5 mRNAs were also found to be down-regulated in LPS models of inflammation. The significant down-regulation of hepatic FMO3 protein during C. rodentium treatment was confirmed with Western blot analysis of liver microsomes from treated animals. Toll-like receptor (TLR) 4 is known to be responsible for LPS signaling in association with several proteins. To investigate whether TLR4 was responsible for regulation of Fmo genes in both LPS and C. rodentium animal models, Fmo mRNA levels in female wild-type (C3H/HeOuJ) and TLR4 mutant (C3H/HeJ) mice were compared in both inflammatory models by real-time RT-PCR. The results showed that Fmo3 down-regulation during C. rodentium infection is independent of TLR4. Whereas TLR4 is likely to play only a partial role in Fmo1 gene regulation in LPS-treated animals, our results show that the down-regulation of Fmo3 and Fmo5 in this model is TLR4-dependent. Unlike cytochrome P450 regulation measured in the same mouse strains, Fmo3 expression was largely refractory to down-regulation in the DSS model of inflammatory colitis.
    Drug metabolism and disposition: the biological fate of chemicals 03/2009; 37(3):462-8. DOI:10.1124/dmd.108.025338 · 3.25 Impact Factor
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