Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease

Phillips, Ian; Shephard, Elizabeth A.

doi:10.1080/00498254.2019.1643515

Cited by 50 publications

(47 citation statements)

References 177 publications

(178 reference statements)

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“…Previous evidence suggested an important implication of HDL metabolism in modulating the association between TMAO and atherosclerosis. Firstly, since the production of TMAO is dependent on liver FMO3 15 , genetic variants of FMO3 have been implicated in a number of diseases 32 and TMA/FMO3/TMAO has been identified as a key pathway 16 , 33 . In particular, expression of FMO3 modifications in LDLR −/− mice alters circulating and hepatic lipid levels 16 .…”

Section: Discussionmentioning

confidence: 99%

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Trimethylamine N-oxide and the reverse cholesterol transport in cardiovascular disease: a cross-sectional study

Bordoni

Samulak

Sawicka

et al. 2020

Sci Rep

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The early atherosclerotic lesions develop by the accumulation of arterial foam cells derived mainly from cholesterol-loaded macrophages. Therefore, cholesterol and cholesteryl ester transfer protein (CETP) have been considered as causative in atherosclerosis. Moreover, recent studies indicate the role of trimethylamine N-oxide (TMAO) in development of cardiovascular disease (CVD). The current study aimed to investigate the association between TMAO and CETP polymorphisms (rs12720922 and rs247616), previously identified as a genetic determinant of circulating CETP, in a population of coronary artery disease (CAD) patients (n = 394) and control subjects (n = 153). We also considered age, sex, trimethylamine (TMA) levels and glomerular filtration rate (GFR) as other factors that can potentially play a role in this complex picture. We found no association of TMAO with genetically determined CETP in a population of CAD patients and control subjects. Moreover, we noticed no differences between CAD patients and control subjects in plasma TMAO levels. On the contrary, lower levels of TMA in CAD patients respect to controls were observed. Our results indicated a significant correlation between GFR and TMAO, but not TMA. The debate whether TMAO can be a harmful, diagnostic or protective marker in CVD needs to be continued.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, we observed no differences between CAD patients and control subjects in plasma TMAO levels, TMAO which can be affected by intra-individual variation 50 . The debate whether TMAO can be a harmful, diagnostic or protective marker in CVD 28 , 29 , 32 has to be continued.…”

Section: Discussionmentioning

confidence: 99%

Trimethylamine N-oxide and the reverse cholesterol transport in cardiovascular disease: a cross-sectional study

Bordoni

Samulak

Sawicka

et al. 2020

Sci Rep

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“…Drug metabolism is strictly connected to genetic polymorphism. Significant differences in drug clearances were previously reported for drug-metabolizing enzymes [33][34][35][36]. Human FMO3 is highly polymorphic since more than 20 single nucleotide polymorphisms (SNPs) were reported for this enzyme in the SNP database (http://www.ncbi.nlm.nih.gov/projects/SNP).…”

Section: Single Nucleotide Polymorphisms Of Hfmo3mentioning

confidence: 99%

“…Human FMO3 is highly polymorphic since more than 20 single nucleotide polymorphisms (SNPs) were reported for this enzyme in the SNP database (http://www.ncbi.nlm.nih.gov/projects/SNP). ASP132HIS, GLY180VAL, GLU158LYS, VAL257MET, VAL277ALA, GLU308GLY and GLU362GLN are the most common hFMO3 variants [33,[37][38][39][40][41][42][43], (Figure 1). The crystal structure of hFMO3 is not available, but molecular modelling can give significant hints on the location of the amino acids on the structure of the enzyme.…”

Section: Single Nucleotide Polymorphisms Of Hfmo3mentioning

confidence: 99%

Enzymatically Produced Trimethylamine N-Oxide: Conserving It or Eliminating It

et al. 2019

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Trimethylamine N-Oxide (TMAO) is the product of the monooxygenation reaction catalyzed by a drug-metabolizing enzyme, human flavin-containing monooxygenase 3 (hFMO3), and its animal orthologues. For several years, researchers have looked at TMAO and hFMO3 as two distinct molecules playing specific but separate roles, the former to defend saltwater animals from osmotic or hydrostatic stress and the latter to process xenobiotics in men. The presence of high levels of plasmatic TMAO in elasmobranchs and other animals was demonstrated a long time ago, whereas the actual physiological role of hFMO3 is still unknown because the enzyme has been mainly characterized for its ability to oxidize drugs. Recently TMAO was found to be related to several human health conditions such as atherosclerosis, cardiovascular, and renal diseases. This correlation poses a striking question of how other vertebrates (and invertebrates) can survive in the presence of very high TMAO concentrations (micromolar in humans, millimolar in marine mammals and several hundred millimolar in elasmobranchs). Therefore, it is important to address how TMAO, its precursors, and FMO catalytic activity are interconnected.

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“…In addition to defective FMO3 causing the inherited disorder primary trimethylaminuria, trimethylamine N-oxide, the product of FMO3-catalyzed oxygenation of trimethylamine, has been associated with several disease states (reviewed in [48,65]). In particular, elevated plasma concentrations of trimethylamine N-oxide have been implicated as a risk factor for cardiovascular disease [66][67][68][69][70].…”

Section: Trimethylaminementioning

confidence: 99%

Endogenous Roles of Mammalian Flavin-Containing Monooxygenases

Phillips

Shephard

2019

Catalysts

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Flavin-containing monooxygenases (FMOs) catalyze the oxygenation of numerous foreign chemicals. This review considers the roles of FMOs in the metabolism of endogenous substrates and in physiological processes, and focuses on FMOs of human and mouse. Tyramine, phenethylamine, trimethylamine, cysteamine, methionine, lipoic acid and lipoamide have been identified as endogenous or dietary-derived substrates of FMOs in vitro. However, with the exception of trimethylamine, the role of FMOs in the metabolism of these compounds in vivo is unclear. The use, as experimental models, of knockout-mouse lines deficient in various Fmo genes has revealed previously unsuspected roles for FMOs in endogenous metabolic processes. FMO1 has been identified as a novel regulator of energy balance that acts to promote metabolic efficiency, and also as being involved in the biosynthesis of taurine, by catalyzing the S-oxygenation of hypotaurine. FMO5 has been identified as a regulator of metabolic ageing and glucose homeostasis that apparently acts by sensing or responding to gut bacteria. Thus, FMOs do not function only as xenobiotic-metabolizing enzymes and there is a risk that exposure to drugs and environmental chemicals that are substrates or inducers of FMOs would perturb the endogenous functions of these enzymes.

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Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease

Cited by 50 publications

References 177 publications

Trimethylamine N-oxide and the reverse cholesterol transport in cardiovascular disease: a cross-sectional study

Trimethylamine N-oxide and the reverse cholesterol transport in cardiovascular disease: a cross-sectional study

Enzymatically Produced Trimethylamine N-Oxide: Conserving It or Eliminating It

Endogenous Roles of Mammalian Flavin-Containing Monooxygenases

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