Ethnic Differences in Human Flavin-Containing Monooxygenase 2 (FMO2) Polymorphisms: Detection of Expressed Protein in African-Americans

Whetstine, Johnathan R.; Yueh, Mei‐Fei; Hopp, Kathleen A.; McCarver, D. Gail; Williams, David E.; Park, C.-S; Kang, Ju‐Hee; Cha, Young‐Nam; Dolphin, Colin T.; Shephard, Elizabeth A.; Phillips, Ian; Hines, Ronald N.

doi:10.1006/taap.2000.9050

Cited by 84 publications

(81 citation statements)

References 34 publications

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“…The nonsense mutation g.23238C>T(Q472X) is not present in our closest relatives, chimpanzee (Pan troglodytes) and gorilla (Gorilla gorilla) [57], and, therefore, arose in the human lineage after the divergence of humans and chimps. The FMO2*2A allele subsequently spread to attain a frequency of essentially 100% in all populations, with the exception of those of recent African descent in which the ancestral allele (FMO2*1), which encodes a full-length polypeptide, is present at appreciable frequencies [57,58]. The presence of full-length active FMO2 in lung microsomes from an FMO2*1 individual has been confirmed [59].…”

Section: Fmo2mentioning

confidence: 88%

Flavin-containing monooxygenases: mutations, disease and drug response

Phillips

Shephard

2008

Trends in Pharmacological Sciences

118

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Section: Fmo2mentioning

confidence: 88%

Flavin-containing monooxygenases: mutations, disease and drug response

Phillips

Shephard

2008

Trends in Pharmacological Sciences

118

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“…One FMO isoenzyme, FMO2, is highly expressed in the lung of rabbits and can account for 10% or more of the total microsomal protein fraction [72]. Humans show genetic polymorphism in the expression of FMO2 in lung [73]. Although it is not known whether the GSH conjugate of acrolein is a substrate for FMO2, it is conceivable that the GSH conjugate is bioactivated in the lung, which could be relevant to acrolein exposure through cigarette smoke.…”

Section: Glutathione Conjugation With Acroleinmentioning

confidence: 99%

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Stevens

Maier

2008

Molecular Nutrition Food Res

633

634

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Acrolein (2-propenal) is ubiquitously present in (cooked) foods and in the environment. It is formed from carbohydrates, vegetable oils and animal fats, amino acids during heating of foods, and by combustion of petroleum fuels and biodiesel. Chemical reactions responsible for release of acrolein include heat-induced dehydration of glycerol, retro-aldol cleavage of dehydrated carbohydrates, lipid peroxidation of polyunsaturated fatty acids, and Strecker degradation of methionine and threonine. Smoking of tobacco products equals or exceeds the total human exposure to acrolein from all other sources. The main endogenous sources of acrolein are myeloperoxidase-mediated degradation of threonine and amine oxidase-mediated degradation of spermine and spermidine, which may constitute a significant source of acrolein in situations of oxidative stress and inflammation. Acrolein is metabolized by conjugation with glutathione and excreted in the urine as mercapturic acid metabolites. Acrolein forms Michael adducts with ascorbic acid in vitro, but the biological relevance of this reaction is not clear. The biological effects of acrolein are a consequence of its reactivity towards biological nucleophiles such as guanine in DNA and cysteine, lysine, histidine, and arginine residues in critical regions of nuclear factors, proteases, and other proteins. Acrolein adduction disrupts the function of these biomacromolecules which may result in mutations, altered gene transcription, and modulation of apoptosis.

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“…Subsequently, Dolphin et al (1998) published the sequence of human FMO2 and documented a very interesting genetic polymorphism in expression. All of the Caucasians and Asians genotyped to date have 2 alleles with a c. 1414C→T transition replacing a Gln (CAG, FMO2*1, p.Q472) with a premature stop codon (TAG, FMO2*2A, p.X472; Dolphin et al, 1998;Whestine et al, 2000;Krueger et al, 2002b;Furnes et al, 2003). This truncated protein is not found in human lung samples; expressed p.X472 does not incorporate FAD, is catalytically inactive, and is probably rapidly destroyed due to incorrect folding (Whestine et al, 2000;Krueger et al, 2002a).…”

Section: Genetic Polymorphisms Of Flavin-containing Monooxygenasementioning

confidence: 99%

“…All of the Caucasians and Asians genotyped to date have 2 alleles with a c. 1414C→T transition replacing a Gln (CAG, FMO2*1, p.Q472) with a premature stop codon (TAG, FMO2*2A, p.X472; Dolphin et al, 1998;Whestine et al, 2000;Krueger et al, 2002b;Furnes et al, 2003). This truncated protein is not found in human lung samples; expressed p.X472 does not incorporate FAD, is catalytically inactive, and is probably rapidly destroyed due to incorrect folding (Whestine et al, 2000;Krueger et al, 2002a). Interestingly, 27% of individuals of African descent (Dolphin et al, 1998;Whestine et al, 2000) and 5% of Hispanics (Krueger et al, 2004) possess at least 1 allele coding for the full length, enzymatically active protein (FMO2.1, p.Q472).…”

Section: Genetic Polymorphisms Of Flavin-containing Monooxygenasementioning

confidence: 99%

“…This truncated protein is not found in human lung samples; expressed p.X472 does not incorporate FAD, is catalytically inactive, and is probably rapidly destroyed due to incorrect folding (Whestine et al, 2000;Krueger et al, 2002a). Interestingly, 27% of individuals of African descent (Dolphin et al, 1998;Whestine et al, 2000) and 5% of Hispanics (Krueger et al, 2004) possess at least 1 allele coding for the full length, enzymatically active protein (FMO2.1, p.Q472). Individuals genotyped as possessing at least 1 FMO2*1 allele express full length, catalytically active protein which can be detected by immunoquantitation.…”

Section: Genetic Polymorphisms Of Flavin-containing Monooxygenasementioning

confidence: 99%

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

Krueger

Williams

2005

Pharmacology & Therapeutics

515

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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Ethnic Differences in Human Flavin-Containing Monooxygenase 2 (FMO2) Polymorphisms: Detection of Expressed Protein in African-Americans

Cited by 84 publications

References 34 publications

Flavin-containing monooxygenases: mutations, disease and drug response

Flavin-containing monooxygenases: mutations, disease and drug response

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

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

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