Drug metabolism by flavin-containing monooxygenases of human and mouse

Phillips, Ian; Shephard, Elizabeth A.

doi:10.1080/17425255.2017.1239718

Cited by 95 publications

(82 citation statements)

References 136 publications

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“…FMOs (EC 1.14.13.8) are best known for their role in the metabolism of xenobiotics, including therapeutic drugs (reviewed in (21)) and foreign chemicals such as organophosphate insecticides (reviewed in (22)). Of the members of the FMO family, FMO1 has the broadest substrate range (reviewed in (22)).…”

Section: Discussionmentioning

confidence: 99%

FMO1 catalyzes the production of taurine from hypotaurine

Shephard

Veeravalli

Phillips

et al. 2019

Preprint

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Taurine is one of the most abundant amino acids in mammalian tissues. It is obtained from the diet and by de novo synthesis, from cysteic acid or hypotaurine. Despite the discovery in 1954 that the oxygenation of hypotaurine produces taurine, the identification of an enzyme catalyzing this reaction has remained elusive. In large part this is due to the incorrect assignment, in 1962, of the enzyme as a NAD-dependent hypotaurine dehydrogenase. For more than 55 years the literature has continued to refer to this enzyme as such. Here we show, both in vivo and in vitro, that the enzyme that oxygenates hypotaurine to produce taurine is flavin-containing monooxygenase 1 (FMO1). Metabolite analysis of the urine of Fmo1-null mice by 1 H NMR spectroscopy revealed a build-up of hypotaurine and a deficit of taurine in comparison with the concentrations of these compounds in the urine of wild-type mice. In vitro assays confirmed that FMO1 of human catalyzes the conversion of hypotaurine to taurine utilizing either NADPH or NADH as co-factor. FMO1 has a wide substrate range and is best known as a xenobiotic-or drug-metabolizing enzyme. The identification that the endogenous molecule hypotaurine is a substrate for the FMO1catalyzed production of taurine resolves a long-standing mystery. This finding should help establish the role FMO1 plays in a range of biological processes in which taurine or its deficiency is implicated, including conjugation of bile acids, neurotransmitter, anti-oxidant and anti-inflammatory functions, the pathogenesis of obesity and skeletal muscle disorders.

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Section: Discussionmentioning

confidence: 99%

FMO1 catalyzes the production of taurine from hypotaurine

Shephard

Veeravalli

Phillips

et al. 2019

Preprint

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“…Humans possess five functional FMOs, designated FMO1-FMO5. FMO1 has the broadest substrate range, followed by FMO3, whereas FMO2 and FMO5 have more restricted ranges of substrates, and almost nothing is known regarding the substrate range of FMO4 (Phillips and Shephard, 2017). Therefore, the FMO isoforms responsible for the formation of M1 require further study.…”

Section: Discussionmentioning

confidence: 99%

“…To the best of our knowledge, the carbonyl reduction reactions catalyzed by FMOs have not been described previously. A recent study reported that human FMO5 could catalyze the oxidation of a wide range of carbonyl compounds via the insertion of an oxygen atom into a carbon-carbon bond adjacent to the carbonyl group to form an ester; however, this enzyme is not involved in reduction (Phillips and Shephard, 2017). The mechanism through which FMOs catalyze carbonyl reductions requires further study.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of F18, a Derivative of Calanolide A, in Human Liver Microsomes and Cytosol

Zhang

Guo

et al. 2017

Front. Pharmacol.

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10-Chloromethyl-11-demethyl-12-oxo-calanolide (F18), an analog of calanolide A, is a novel potent nonnucleoside reverse transcriptase inhibitor against HIV-1. Here, we report the metabolic profile and the results of associated biochemical studies of F18 in vitro and in vivo. The metabolites of F18 were identified based on liquid chromatography-electrospray ionization mass spectrometry and/or nuclear magnetic resonance. Twenty-three metabolites of F18 were observed in liver microsomes in vitro. The metabolism of F18 involved 4-propyl chain oxidation, 10-chloromethyl oxidative dechlorination and 12-carbonyl reduction. Three metabolites (M1, M3-1, and M3-2) were also found in rat blood after oral administration of F18 and the reduction metabolites M3-1 and M3-2 were found to exhibit high potency for the inhibition of HIV-1 in vitro. The oxidative metabolism of F18 was mainly catalyzed by cytochrome P450 3A4 in human microsomes, whereas flavin-containing monooxygenases and 11β-hydroxysteroid dehydrogenase were found to be involved in its carbonyl reduction. In human cytosol, multiple carbonyl reductases, including aldo-keto reductase 1C, short-chain dehydrogenases/reductases and quinone oxidoreductase 1, were demonstrated to be responsible for F18 carbonyl reduction. In conclusion, the in vitro metabolism of F18 involves multiple drug metabolizing enzymes, and several metabolites exhibited anti-HIV-1 activities. Notably, the described results provide the first demonstration of the capability of FMOs for carbonyl reduction.

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“…Over the last few years, it has become increasingly clear that there are significant differences in drug metabolism related to polymorphisms of drug‐metabolising enzymes including the hepatic hFMO3 (human flavin‐containing monooxygenase isoform 3) . This enzyme is known to be highly polymorphic with more than 20 single nucleotide polymorphisms (SNPs) deposited in the SNP database (http://www.ncbi.nlm.nih.gov/projects/SNP).…”

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confidence: 99%

Flavin‐Containing Monooxygenase 3 Polymorphic Variants Significantly Affect Clearance of Tamoxifen and Clomiphene

Catucci

Bortolussi

Rampolla

et al. 2018

Basic Clin Pharma Tox

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Human flavin-containing monooxygenase 3 (hFMO3) is a drug-metabolising enzyme that oxygenates many drugs and xenobiotics in the liver. This enzyme is also known to exhibit single nucleotide polymorphisms (SNPs) that can alter the rates of monooxygenation of therapeutic agents. The purpose of this study was to investigate the effect of the three common polymorphic variants of hFMO3 (V257M, E158K and E308G) on the metabolism and clearance of three structurally similar compounds: tamoxifen (breast cancer medication), clomiphene (infertility medication) and GSK5182 (antidiabetic lead molecule). For GSK5182, none of the three variants showed any significant differences in its metabolism when compared to the wild-type enzyme. In the case of clomiphene, two of the variants, V257M and E308G, exhibited a significant increase in all the kinetic parameters measured with nearly two times faster clearance. Finally, for tamoxifen, a mixed behaviour was observed; E158K variant showed a significantly higher clearance compared to the wild type, whereas V257M mutation had the opposite effect. Overall, the data obtained demonstrate that there is no direct correlation between the SNPs and the metabolism of these three hFMO3 substrates. The metabolic capacity is both variant-dependent and substrate-dependent and therefore when testing new drugs or administering already approved therapies, these differences should be taken into consideration.

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Drug metabolism by flavin-containing monooxygenases of human and mouse

Cited by 95 publications

References 136 publications

FMO1 catalyzes the production of taurine from hypotaurine

FMO1 catalyzes the production of taurine from hypotaurine

Metabolism of F18, a Derivative of Calanolide A, in Human Liver Microsomes and Cytosol

Flavin‐Containing Monooxygenase 3 Polymorphic Variants Significantly Affect Clearance of Tamoxifen and Clomiphene

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