Flavin-containing monooxygenase mediated metabolism of psychoactive drugs by human brain microsomes

Bhamre, Shubhada; Bhagwat, Shripad V.; Shankar, Susarla Krishna; Boyd, Michael R.; Ravindranath, Vijayalakshmi

doi:10.1016/0006-8993(94)01135-5

Cited by 37 publications

(23 citation statements)

References 11 publications

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“…Overall, FMO mRNA levels in brain are much lower than those in most other tissues examined, and at the level of less than 1% as compared to the most abundant tissues observed (i.e., FMO1 in kidney, FMO2 in lung, and FMO3 and 5 in liver). Although FMO functional activity has been reported in animal (Bhamre et al, 1993(Bhamre et al, , 1995Kawaji et al, 1995) and human brain (Bhamre et al, 1995;Bhagwat et al, 1996), based on the data herein, it is not clear whether FMOs make a significant contribution to functional chemical metabolism in human brain. This study focuses on brain tissue from the substantia nigra where FMO has been reported (Cashman and Zhang, 2002); other regions of the brain may be selectively enriched in FMO.…”

Section: Discussionmentioning

confidence: 58%

QUANTITATIVE ANALYSIS OF FMO GENE mRNA LEVELS IN HUMAN TISSUES

Zhang

Cashman²

2005

Drug Metab Dispos

125

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ABSTRACT:The developmentally and tissue-specific expression of flavin-containing monooxygenase (FMO) enzymes has been previously characterized in a number of animal species, including humans, mice, rats, and rabbits. In this study, we used sensitive real-time reverse transcription-polymerase chain reaction methodology to systematically quantify the steady-state mRNA levels of FMO1, 2, 3, 4, and 5 in human tissues. We examined the developmental regulation of these enzymes in brain tissue. FMO1 was found to be downregulated in human adult brain. The amount of other FMO mRNAs in human brains in different age groups was not significantly different. The study also provided a systematic quantitative comparison of the steady-state mRNA levels of FMO1 to 5 in several major human organs (i.e., liver, lung, kidney, small intestine, and brain).The nature of the quantitative analysis allowed a comprehensive comparison of each FMO mRNA in different tissues as well as among FMO isoforms in the same tissue. A comparison between fetal liver and adult liver showed that FMO1 was the only FMO that was down-regulated; all other FMOs had greater amounts of mRNA in adult liver. FMO5 was the most prominent FMO form detected in fetal liver. The FMO5 mRNA level was nearly as abundant as FMO3 in adult liver. Whereas other FMOs displayed a significant, dominant tissue-specific mRNA profile (i.e., FMO1 in kidney, FMO2 in lung, FMO3 and FMO5 in adult liver), FMO4 mRNA was observed more broadly at relatively comparable levels in liver, kidney, lung, and small intestine.Flavin-containing monooxygenases (FMOs) (EC 1.14.13.8) are a family of NADPH-and FAD-dependent enzymes that catalyze the oxygenation of a wide variety of compounds containing nucleophilic nitrogen, sulfur, and phosphorous heteroatoms (Ziegler, 1988;Cashman, 1995). The enzyme is recognized as a broad spectrum monooxygenase, and functional diversity of this family is determined by the expression of five FMO genes, named FMO1 to FMO5, and their variants. There are also a large number of FMO splice variants detected in human tissue (Lattard et al., 2004). A number of other FMO pseudogenes have been described, but apparently no other functional proteins are expressed Hernandez et al., 2004).The developmentally and tissue-specific expression of FMOs has been characterized in a number of animal species, including humans, mice, rats, and rabbits (Hines et al., 1994). Methods that have been used to characterize FMO expression include RNase protection assays for FMOs in human kidney and liver (Dolphin et al., 1996) and mouse to quantify mRNA, Western blot analysis in human liver to quantify protein level (Koukouritaki et al., 2002), and microsomal activity measurements for human liver FMO (Overby et al., 1997) and rabbit FMOs (Shehin-Johnson et al., 1995). The functional characterization of FMO previously reported has mainly focused on hepatic-and kidney-mediated metabolism, where the majority of the metabolism of drugs and exogenous chemicals occur. Limited animal studies, mostly us...

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Section: Discussionmentioning

confidence: 58%

QUANTITATIVE ANALYSIS OF FMO GENE mRNA LEVELS IN HUMAN TISSUES

Zhang

Cashman²

2005

Drug Metab Dispos

125

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“…In the human brain, FMO3 is a prominent form, but human FMO4 and FMO5 are also present and, depending on the region of the brain, may represent major or minor isoforms (Bhamre et al, 1995). By a combination of immunological and reverse transcription-polymerase chain reaction methods, we have determined that in human substantia nigra, FMO3 is the prominent form, and FMO4 is present to a less extent (unpublished results).…”

Section: Downloaded Frommentioning

confidence: 88%

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

Cashman¹,

Zhang²

2002

Drug Metab Dispos

100

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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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“…The oximes appear to have little pharmacological activity, and therefore FMO-mediated N-oxygenation of biogenic amines appears to be a mechanism for inactivation. Brain contains active FMO (Bhamre et al, 1993(Bhamre et al, , 1995Bhagwat et al, 1996aBhagwat et al, , 1996bBlake et al, 1996;Kawaji et al, 1997) and conversion of biogenic amines in the brain by FMO (Lin & Cashman, 1997a) could be of clinical significance.…”

Section: Nitrogen-containing Endogenous Substrates-mentioning

confidence: 99%

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

Krueger

Williams

2005

Pharmacology & Therapeutics

493

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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Flavin-containing monooxygenase mediated metabolism of psychoactive drugs by human brain microsomes

Cited by 37 publications

References 11 publications

QUANTITATIVE ANALYSIS OF FMO GENE mRNA LEVELS IN HUMAN TISSUES

QUANTITATIVE ANALYSIS OF FMO GENE mRNA LEVELS IN HUMAN TISSUES

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

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

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