Ethnic differences in allelic frequency of two flavin-containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities

Park, Chang‐Shin; Kang, Ju‐Hee; Chung, Won Gyun; Yi, Hyun-Gyu; Pie, Jae-Eun; Park, Dong-Kyun; Hines, Ronald N.; McCarver, D. Gail; Cha, Young‐Nam

doi:10.1097/00008571-200201000-00011

Cited by 52 publications

(53 citation statements)

References 8 publications

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“…Studies in vitro with expressed FMO enzymes have shown FMO3 to be selective in the Noxygenation of trimethylamine (Lang et al, 1998). A number of allelic variants have been associated with the incidence and severity of TMAU in patients (Zhang et al, 1996Cashman et al, 1997Cashman et al, , 2000Cashman et al, , 2001Cashman et al, , 2003Dolphin et al, 1997;Kang et al, 2000;Murphy et al, 2000;Forrest et al, 2001;Cashman, 2002;Cashman & Zhang, 2002;Park et al, 2002;Hernandez et al, 2003;Lattard et al, 2003aLattard et al, , 2003b. These individuals can be diagnosed by urinary ratios of trimethylamine N-oxide to trimethylamine following a challenge dose of choline.…”

Section: Genetic Variants In Flavin-containing Monooxygenase 3 and Trmentioning

confidence: 99%

“…Of particular significance for this review is that individuals homozygous for certain FMO3 allelic variants (e.g., null variants) also demonstrate impaired metabolism toward other FMO substrates including ranitidine, nicotine, thio-benzamide, and phenothiazine derivatives (Table 4; Cashman et al, 1995Cashman et al, ,2000Kang et al, 2000;Cashman, 2002;Park et al, 2002;Lattard et al, 2003aLattard et al, ,2003b. The rare null variants are present in patients with TMAU, whereas variants resulting in a less efficient enzyme (e.g., E158K, E308G) may not exhibit a phenotype.…”

Section: Genetic Variants In Flavin-containing Monooxygenase 3 and Trmentioning

confidence: 99%

“…However, subsequent examination has raised serious doubts about the utility of caffeine for FMO phenotyping . Ranitidine metabolism correlates with FMO3 phenotype (Park et al, 2002) and may provide promise in phenotyping individuals for metabolism of other FMO3 substrates.…”

Section: Role Of Flavin-containing Monooxygenase In Drug Metabolismmentioning

confidence: 99%

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Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

515

444

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Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "softnucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

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Section: Genetic Variants In Flavin-containing Monooxygenase 3 and Trmentioning

confidence: 99%

Section: Genetic Variants In Flavin-containing Monooxygenase 3 and Trmentioning

confidence: 99%

See 1 more Smart Citation

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Krueger

Williams

2005

Pharmacology & Therapeutics

515

444

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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%

“…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]. Homozygotes for 158K/308G can exhibit symptoms of mild or transient TMAuria [47,48].…”

Section: Fmo3mentioning

confidence: 99%

Flavin-containing monooxygenases: mutations, disease and drug response

Phillips

Shephard

2008

Trends in Pharmacological Sciences

118

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Development of a physiologically based pharmacokinetic model to predict the effects of flavin‐containing monooxygenase 3 (FMO3) polymorphisms on itopride exposure

Zhou

Humphries

Gardner

et al. 2017

Biopharm & Drug Disp

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Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on the frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles. Individuals with homozygous Lys158 and Gly308 mutations account for about 5% of the total population in Asian populations. A CL of 9 μl/min/pmol was optimised for itopride via a retrograde approach as human liver microsomal results would under-predict its clearance by ~7.9-fold. The developed itopride PBPK model was first verified with three additional clinical studies in Korean and Japanese subjects resulting in a predicted clearance of 52 to 69 l/h, which was comparable to those observed (55 to 88 l/h). The model was then applied to predict plasma concentration-time profiles of itopride in Chinese subjects with wild type or homozygous Lys158 and Gly308 FMO3 genotypes. The ratios of predicted to observed AUC of itopride in subjects with each genotype were 1.23 and 0.94, respectively. In addition, the results also suggested that for FMO3 metabolised drugs with a safety margin of 2 or more, proactive genotyping FMO3 to exclude subjects with homozygous Lys158/Gly308 alleles may not be necessary.

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Ethnic differences in allelic frequency of two flavin-containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities

Cited by 52 publications

References 8 publications

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Flavin-containing monooxygenases: mutations, disease and drug response

Development of a physiologically based pharmacokinetic model to predict the effects of flavin‐containing monooxygenase 3 (FMO3) polymorphisms on itopride exposure

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