Studies on the discontinuous N-oxidation of trimethylamine among Jordanian, Ecuadorian and New Guinean populations

Mitchell, Stephen C.; Zhang, A Q; Barrett, Tyler M.; Ayesh, R.; Smith, Richard L.

doi:10.1097/00008571-199702000-00006

Cited by 34 publications

(21 citation statements)

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“…Trimethylamine is formed endogenously from the breakdown of choline and the reduction of trimethylamine N-oxide present in high concentrations in diets rich in fish. Trimethylamine is normally metabolized to the N-oxide, a metabolite with no detectable offensive odor, by FMO in the liver (Sardas et al, 1996;Mitchell et al, 1997). Studies in vitro with expressed FMO enzymes have shown FMO3 to be selective in the Noxygenation of trimethylamine (Lang et al, 1998).…”

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

confidence: 99%

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

Krueger

Williams

2005

Pharmacology & Therapeutics

503

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%

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

Krueger

Williams

2005

Pharmacology & Therapeutics

503

444

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“…The incidence of heterozygotes in British Caucasians is about 1%, but in other populations it might be considerably higher [19]. More than 30 distinct causative mutations have been identified (Figure 3) [3,18,20].…”

Section: Fmo3 and Tmauriamentioning

confidence: 99%

Flavin-containing monooxygenases: mutations, disease and drug response

Phillips

Shephard

2008

Trends in Pharmacological Sciences

117

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“…Trimethylaminuria is an uncommon disease that is nonrandomly distributed in the population. However, in some parts of the world, especially in the tropics, there appears to be an elevated incidence of trimethylaminuria (Al-Waiz et al, 1987;Hadidi et al, 1995;Dolphin et al, 1997a;Mitchell et al, 1997;Thithapandha, 1997;Treacy et al, 1998). Individuals with trimethylaminuria possess a decreased ability to oxygenate diet-derived TMA.…”

Section: Rare Human Fmo3 Mutationsmentioning

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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Studies on the discontinuous N-oxidation of trimethylamine among Jordanian, Ecuadorian and New Guinean populations

Cited by 34 publications

References 0 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

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

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