A series of simple detection systems for genetic variants of flavin-containing monooxygenase 3 (FMO3) with impaired function in Japanese subjects

Shimizu, Makiko; Mizugaki, Ami; Koibuchi, Natsumi; Sango, Haruna; Uenuma, Yumi; Yamazaki, Hiroshi

doi:10.1016/j.dmpk.2021.100420

Cited by 7 publications

(6 citation statements)

References 60 publications

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“…The wild-type human FMO3 enzyme has 532 amino acids (Fig. 3), but some genetic polymorphisms in FMO3 encode naturally truncated forms that have little or no detectable functional enzymatic activity (Yamazaki et al, 2007;Shimizu et al, 2021b) because they are insufficient anchors to membranes that boost FMO3 function. The deleterious effects of the C-terminal stop codons (from Glu305 and Arg500 positions) on recombinant truncated FMO3 variant-mediated drug N-oxygenation (Yamazaki et al, 2007;Enna, 2012) suggest that truncated FMO3 variants Val187SerfsTer25, Arg238Ter, Lys416SerfsTer72, and Gln427Ter…”

Section: Discussionmentioning

confidence: 99%

“…variants that were already recorded in the National Center for Biotechnology Information (NCBI) database with individual rs numbers were newly identified in the updated 38K JPN database (Table 1). Moreover, four functionally known amino-acid-substituted FMO3 variants, namely FMO3 p.Ser195Leu, p.Arg223Gln, and p.Ile441Thr [found in Japanese families (Shimizu et al, 2021b)] and FMO3 p.Asn61Ser [reported in European families (Dolphin et al, 2000)] were also found in the updated 38K JPN database. Among the 24 already known amino-acid substituted FMO3 variants, FMO3 p.Ile37Thr (Teresa et al, 2006) and p.Arg387His (Kilic, 2017) have been reported in the literature, but their catalytic function remains unknown.…”

Section: New Fmo3 Variantsmentioning

confidence: 99%

“…An increasing number of single-nucleotide substitutions in the human FMO3 gene are being recorded in mega-databases (Shimizu et al, 2019b;Shimizu et al, 2021a;. Furthermore, a series of reliable FMO3 genotyping confirmation methods has been assembled and developed for approximately 40 impaired FMO3 variants (Shimizu et al, 2021b). The Japanese population reference panel of the Tohoku Medical Megabank Organization's biobank was increased to 38,000 subjects (38K JPN) in 2022 from the previous panel that covered 8300 subjects (previous panels were known as 3.5K, 4.7K, and 8.3K JPN) (Shimizu et al, 2019b;Shimizu et al, 2021a;Shimizu et al, 2022).…”

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confidence: 99%

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Variants of Flavin-Containing Monooxygenase 3 Found in Subjects in an Updated Database of Genome Resources

et al. 2023

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Single-nucleotide substitutions of human flavin-containing monooxygenase 3 (FMO3) identified in the whole-genome sequences of the updated Japanese population reference panel (now containing 38,000 subjects) were investigated. In this study, 2 stop codon mutations, 2 frameshifts, and 43 amino-acid-substituted FMO3 variants were identified. Among these 47 variants, 1 stop codon mutation, 1 frameshift, and 24 substituted variants were already recorded in the National Center for Biotechnology Information database. Functionally impaired FMO3 variants are known to be associated with the metabolic disorder trimethylaminuria; consequently, the enzymatic activities of the 43 substituted FMO3 variants were investigated. Twenty-seven recombinant FMO3 variants expressed in bacterial membranes had similar activities toward trimethylamine N-oxygenation (~75-125%) to that of wild-type FMO3 (98 min -1 ). However, 6 recombinant FMO3 variants (Arg51Gly, Val283Ala, Asp286His, Val382Ala, Arg387His, and Phe451Leu) had moderately decreased (≈50%) activities toward trimethylamine N-oxygenation, and 10 recombinant FMO3 variants (Gly11Asp,

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Section: Discussionmentioning

confidence: 99%

Section: New Fmo3 Variantsmentioning

confidence: 99%

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Variants of Flavin-Containing Monooxygenase 3 Found in Subjects in an Updated Database of Genome Resources

et al. 2023

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“…Various methods have been proposed to analyze the targeted SNPs. For example, FMO3 -related SNPs have been detected by using PCR-restriction fragment length polymorphism analysis ( 19 ), real-time PCR ( 20 ) and direct sequencing methods ( 21 ). Sequencing technology was first conceptualized and developed in the 1970s by Sanger et al ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Rapid detection ofFMO3single nucleotide polymorphisms using a pyrosequencing method

Park

Kim

et al. 2021

Mol Med Rep

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The present study aimed to develop a reliable pyrosequencing method to detect four single nucleotide polymorphisms (SnPs) of the flavin-containing monooxygenase 3 (FMO3) gene and to compare the ethnic differences in their allelic frequencies. The pyrosequencing method was used to detect four FMO3 SnPs, namely, c.855c>T (n285n, rs909530), c.441c>T (S147S, rs1800822), c.923a>G (e308G, rs2266780) and c.472G>a (e158K, rs2266782). The allelic frequencies of these SnPs in 122 unrelated Korean subjects were as follows: i) 44.7% for c.855c>T; ii) 23.4% for c.441c>T; iii) 23.0% for c.923a>G; and iv) 27.1% for c.472G>a. linkage disequilibrium (ld) analysis revealed that the SnPs c.923a>G and c.472G>a exhibited a strong ld (d'=0.8289, r 2 =0.5332). in conclusion, the pyrosequencing method developed in this study was successfully applied to detect the c.855c>T, c.441c>T, c.923a>G and c.472G>a SnPs of FMO3.

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“…Increasing numbers of single-nucleotide substitutions of the human FMO3 gene are being recorded in mega-databases (Shimizu et al, 2019). A series of reliable FMO3 genotyping confirmation methods has been assembled and developed for ~40 impaired FMO3 variants (Shimizu et al, 2021a). This series of systems should facilitate the easy detection in the clinical setting of FMO3 variants in subjects susceptible to low drug clearances or drug interactions possibly caused by impaired FMO3 function.…”

Section: Some Key Recent Advancesmentioning

confidence: 99%

Species Specificity and Selection of Models for Drug Oxidations Mediated by Polymorphic Human Enzymes

Yamazaki

Shimizu

2022

Drug Metab Dispos

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Many drug oxygenations are mainly mediated by polymorphic cytochromes P450 (P450s) and also by flavin-containing monooxygenases (FMOs). More than 50 years of research on P450/FMO-mediated drug oxygenations have clarified their catalytic roles. The natural product coumarin causes hepatotoxicity in rats via the reactive coumarin 3,4-epoxide, a reaction catalyzed by P450 1A2; however, coumarin undergoes rapid 7-hydroxylation by polymorphic P450 2A6 in humans. The primary oxidation product of the teratogen thalidomide in rats is deactivated 5′-hydroxythalidomide plus sulfate and glucuronide conjugates; however, similar 5′-hydroxythalidomide and 5-hydroxythalidomide are formed in rabbits in vivo. Thalidomide causes human P450 3A enzyme induction in liver (and placenta) and is also activated in vitro and in vivo by P450 3A through the primary human metabolite 5-hydroxythalidomide (leading to conjugation with glutathione/nonspecific proteins). Species differences exist in terms of drug metabolism in rodents and humans, and such differences can be very important when determining the contributions of individual enzymes. The approaches used for investigating the roles of human P450 and FMO enzymes in understanding drug oxidations and clinical therapy have not yet reached maturity and still require further development.

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A series of simple detection systems for genetic variants of flavin-containing monooxygenase 3 (FMO3) with impaired function in Japanese subjects

Cited by 7 publications

References 60 publications

Variants of Flavin-Containing Monooxygenase 3 Found in Subjects in an Updated Database of Genome Resources

Variants of Flavin-Containing Monooxygenase 3 Found in Subjects in an Updated Database of Genome Resources

Rapid detection ofFMO3single nucleotide polymorphisms using a pyrosequencing method

Species Specificity and Selection of Models for Drug Oxidations Mediated by Polymorphic Human Enzymes

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