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

Abstract

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...

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

“…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.…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…The remainder is due to flavin-containing mono-oxygenases 75 that also exhibit genetic polymorphism with resultant variations in catalytic activity. 76 Voriconazole is also a low-affinity substrate for UGT1A4 in vitro. 49 An understanding of how genetic polymorphism affects voriconazole metabolism has been pivotal in explaining the pharmacokinetic variability observed in patients.…”

Effect of pregnancy on a measure of FMO3 activity

“…Six FMO genes exist in humans, but only FMO3 enzyme is abundantly expressed in human liver. FMO3 contributes to the metabolism of several drugs including methimazole, nicotine, cimetidine, ranitidine, tamoxifen, and clozapine [1,2]. Dysfunctional FMO3 enzymes with deficient N-oxygenation of dietary trimethylamine cause trimethylaminuria (fish-odour syndrome).…”

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Flavin-containing monooxygenases (FMO) are a family of microsomal enzymes that catalyse the oxygenation of xenobiotics [1]. Six FMO genes exist in humans, but only FMO3 enzyme is abundantly expressed in human liver.

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“…Methimazole, an antithyroid agent and FMO3 inhibitor, has been reported to reduce nicotine N ¢ -oxide excretion [6]. Thus, formation of nicotine N ¢ -oxide can be used as a probe of human FMO3 activity [1].We recently published a study on pregnant smokers investigating the effect of pregnancy on nicotine and cotinine metabolism [7]. Ten subjects were given deuterium-labelled nicotine-d 2 and cotinine-d 4 infusion (30 or 45 m g/kg -1 of each compound) during pregnancy and postpartum.…”