Flavin monooxygenase 3 (FMO3) polymorphism in a white population: Allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism*1

Sachse, Christoph; Ruschen, S; Dettling, Michael; Schley, J; Bauer, Steffen; Müller‐Oerlinghausen, B.; Roots, Ivar; Brockmöller, Jürgen

doi:10.1053/cp.1999.v66.a102203

Cited by 52 publications

(31 citation statements)

References 12 publications

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“…By contrast, the L360 P polymorphism has been shown to increase the catalytic efficiency of FMO3 [30,31]. In addition, Sachse and colleagues, using a population-based analysis model, did not establish a clear link between certain FMO3 polymorphisms and the metabolism of clozapine or caffeine, suggesting that the mutations examined have only minor functional effects, or that substrate affinity may be too low to be clinically relevant [17]. Of the several variants, the E158K, E308G and V257M polymorphisms have been shown to have a relatively high population distribution [27].…”

Section: Effects Of Fmo3 Polymorphisms On Substrate Metabolism In Vitromentioning

confidence: 99%

“…Ryu and colleagues showed that overproduction of nitric oxide in the liver may suppress FMO3 activity directly via reversible S-nitrosylation [37]. N-oxygenation of nicotine [38], clozapine [17] and the histamine 2 receptor (H 2 ) blockers, cimetidine [39] and ranitidine [40], have all been used to phenotype patient populations with FMO3 variants.…”

Section: In Vivo Effects Of Fmo3 Polymorphismsmentioning

confidence: 99%

“…Its structure and function and the implications of its polymorphisms have been widely studied [8,12,13]. This enzyme has a wide substrate specificity, including the dietary-derived tertiary amines trimethylamine, tyramine and nicotine; commonly used drugs including cimetidine, ranitidine, clozapine, methimazole, itopride, ketoconazole, tamoxifen and sulindac sulfide; and agrichemicals, such as organophosphates and carbamates [14][15][16][17][18][19][20][21][22].…”

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Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Hisamuddin

Yang

2007

Pharmacogenomics

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Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases. Keywords chemoprevention; familial adenomatous polyposis; flavin-containing monooxygenase 3; gastrointestinal diseases; SNP; sulindac sulfide; trimethylaminuria Humans metabolize a vast array of endogenous and exogenous compounds, including drugs and xenobiotics. It has been observed that different individuals, genders and ethnicities respond differently to the same compounds. This has been attributed to multiple factors, one of which is SNPs. With the completion of the human genome sequence and the discovery of existing SNPs in the genome, interest has focused on the role of genetic polymorphisms of enzymeencoding genes involved in the metabolism of both endogenous and exogenous substances.The flavin-containing monooxygenases (FMOs) belong to a family of flavoprotein enzymes that catalyze the oxidation of a broad array of nucleophilic heteroatom-containing drugs, pesticides and chemicals [1][2][3][4]. There are six human isoforms of flavin-containing monooxygenases, of which five are functional. An additional gene cluster containing five pseudogenes has also been identified in both the human and mouse genome [5][6][7][8][9][10].

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Section: Effects Of Fmo3 Polymorphisms On Substrate Metabolism In Vitromentioning

confidence: 99%

Section: In Vivo Effects Of Fmo3 Polymorphismsmentioning

confidence: 99%

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Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Hisamuddin

Yang

2007

Pharmacogenomics

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“…In Europeans and Asians the two most common SNPs, g.15167G>A(E158K) [15,42] and g.21443A>G(E308G) [16], are often linked, occurring on the same chromosome [43][44][45][46]. The compound variant (E158K/E308G) can result in a reduction of enzyme activity, the extent of which depends on the substrate [2][3][4]38,40,41,46].…”

Section: Fmo3mentioning

confidence: 99%

Flavin-containing monooxygenases: mutations, disease and drug response

Phillips

Shephard

2008

Trends in Pharmacological Sciences

117

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“…Oxygenation of (S)-nicotine (Park et al, 1993), TMA (Treacy et al, 1998), cimetidine (Cashman et al, 1993a), clozapine (Sachse et al, 1999), and ranitidine have been used to phenotype various populations for human FMO3 activity. All five materials have been shown to be relatively selective probes of human FMO3 activity in vitro.…”

Section: Interindividual Variability Of Human Fmo3 Functional Activitmentioning

confidence: 99%

Interindividual Differences of Human Flavin-Containing Monooxygenase 3: Genetic Polymorphisms and Functional Variation

Cashman¹,

Zhang²

2002

Drug Metab Dispos

101

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ABSTRACT:The human flavin-containing monooxygenase (form 3) (FMO3) participates in the oxygenation of nucleophilic heteroatom-containing drugs, xenobiotics, and endogenous materials. Currently, six forms of the FMO gene are known, but it is FMO3 that is the major form in adult human liver that is likely responsible for the majority of FMO-mediated metabolism. The substrate structural feature requirements for human FMO3 is beginning to become known to a greater extent and a few chemicals extensively metabolized by FMO3 have been reported. Expression of FMO3 is species-and tissue-specific, but unlike human cytochrome P450, mammalian FMO3 does not appear to be inducible. Interindividual variation in FMO3-dependent metabolism of drugs, chemicals, and endogenous material is therefore more likely due to genetic effects and not environmental ones. Examples of such interindividual variation come from the study of very rare mutations of the human The flavin-containing monooxygenases (FMOs 1 ) (E.C.1.14.13.8) constitute a family of FAD-, NADPH-, and O 2 -dependent microsomal enzymes that catalyze the oxygenation of many nitrogen-, sulfur-, phosphorous-, selenium-, and other nucleophilic heteroatom-containing chemicals (Ziegler, 1980), drugs (Cashman, 1995), and agrichemicals (Hajjar and Hodgson, 1982). There are as many as six forms of mammalian FMO, and some can be present in multiple tissues of the same organism. Some of this information has been previously summarized (Cashman, 2002a). In humans, there is considerable interindividual and interethnic variability in the levels of FMO. In the past few years, a considerable increase in our understanding of the genetic variability of human FMO has occurred and a summary of the current picture focusing on FMO3 will be presented.Evidence for five functional forms of human FMO exist, each encoded by its own gene, that exhibit between 50 to 58% amino acid identity across species lines (Lawton et al., 1994). With the deposit of FMO6 into GenBank, an analysis of the protein encoded by this gene revealed that this protein shares 70% amino acid sequence identity with human FMO3, however, no function for this gene has been described. The description of multiple forms of FMO was advanced by elucidation of the primary sequences by amino acid (Ozols, 1990;Korsmeyer et al., 1998) and nucleotide analysis Lawton et al., 1994;Phillips et al., 1995). As human FMOs were discovered, the common names assigned to enzymes were formalized and a nomenclature was adopted Lawton et al., 1994). The nomenclature was developed on the basis of nucleotide sequence identity. If a human FMO gene has a sequence with Ն82% identity, it is grouped within a family, and the family is indicated by the first numeral of the designation (i.e., 1, 2, 3. . .). The order of naming followed the chronology of publication of the sequence for each member of the family (Dolphin et al., 1997b). The italicized prefix "FMO" is used to designate the gene or an allelic variant. Allelic variants have been observed for FMO that usu...

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Flavin monooxygenase 3 (FMO3) polymorphism in a white population: Allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism*1

Abstract: There are several genetic polymorphisms for the FMO3 enzyme. The effects on the metabolism of caffeine or clozapine could not be shown, indicating that the mutations have only minor functional effects or that substrate affinity is too low to be clinically relevant.

Cited by 52 publications

References 12 publications

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Flavin-containing monooxygenases: mutations, disease and drug response

Interindividual Differences of Human Flavin-Containing Monooxygenase 3: Genetic Polymorphisms and Functional Variation

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