Mammalian flavin-containing monooxygenase (FMO) as a source of hydrogen peroxide

被引:60
作者
Siddens, Lisbeth K.
Krueger, Sharon K. [1 ]
Henderson, Marilyn C.
Williams, David E. [1 ]
机构
[1] Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA
关键词
Flavin-containing monooxygenase; Hydrogen peroxide; Pulmonary FMO2; Oxidative stress; Genetic polymorphism; SUBSTRATE SPECIFICITIES; GENETIC POLYMORPHISMS; EXPRESSED PROTEIN; DRUG-METABOLISM; HUMAN LUNG; MECHANISM; TRIMETHYLAMINURIA; OXYGENATION; OXIDATION; VARIANTS;
D O I
10.1016/j.bcp.2014.02.006
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Flavin-containing monooxygenase (FMO) oxygenates drugs/xenobiotics containing a soft nucleophile through a C4a hydroperoxy-FAD intermediate. Human FMOs 1, 2 and 3, expressed in Sf9 insect microsomes, released 30-50% of 02 consumed as H2O2 upon addition of NADPH. Addition of substrate had little effect on H2O2 production. Two common FMO2 (the major isoform in the lung) genetic polymorphisms, S195L and N413K, were examined for generation of H2O2. FMO2 S195L exhibited higher "leakage", producing much greater amounts of H2O2, than ancestral FMO2 (FMO2.1) or the N413K variant. S195L was distinct in that H2O2 generation was much higher in the absence of substrate. Addition of superoxide dismutase did not impact H2O2 release. Catalase did not reduce levels of H2O2 with either FMO2.1 or FMO3 but inhibited H2O2 generated by FMO2 allelic variants N413K and S195L. These data are consistent with FMO molecular models. S195L resides in the GxGx (S) under barG/A NADP(+) binding motif, in which serine is highly conserved (76/89 known FMOs). We hypothesize that FMO, especially allelic variants such as FMO2 S195L, may enhance the toxicity of xenobiotics such as thioureas/ thiocarbamides both by generation of sulfenic and sulfinic acid metabolites and enhanced release of reactive oxygen species (ROS) in the form of H2O2. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:141 / 147
页数:7
相关论文
共 45 条
[1]   Revealing the moonlighting role of NADP in the structure of a flavin-containing monooxygenase [J].
Alfieri, Andrea ;
Malito, Enrico ;
Orru, Roberto ;
Fraaije, Marco W. ;
Mattevi, Andrea .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (18) :6572-6577
[2]   Membrane transport of hydrogen peroxide [J].
Bienert, Gerd P. ;
Schjoerring, Jan K. ;
Jahn, Thomas P. .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2006, 1758 (08) :994-1003
[3]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[4]   Human flavin-containing monooxygenases [J].
Cashman, JR ;
Zhang, J .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2006, 46 :65-100
[5]   STRUCTURAL AND CATALYTIC PROPERTIES OF THE MAMMALIAN FLAVIN-CONTAINING MONOOXYGENASE [J].
CASHMAN, JR .
CHEMICAL RESEARCH IN TOXICOLOGY, 1995, 8 (02) :165-181
[6]   The flavin-containing monooxygenase 2 gene (FMO2) of humans, but not of other primates, encodes a truncated, nonfunctional protein [J].
Dolphin, CT ;
Beckett, DJ ;
Janmohamed, A ;
Cullingford, TE ;
Smith, RL ;
Shephard, EA ;
Phillips, IR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (46) :30599-30607
[7]   Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome [J].
Dolphin, CT ;
Janmohamed, A ;
Smith, RL ;
Shephard, EA ;
Phillips, IR .
NATURE GENETICS, 1997, 17 (04) :491-494
[8]   Mechanism of action of a flavin-containing monooxygenase [J].
Eswaramoorthy, Subramaniam ;
Bonanno, Jeffrey B. ;
Burley, Stephen K. ;
Swaminathan, Subramanyam .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (26) :9832-9837
[9]   Human Flavin-Containing Monooxygenase 2.1 Catalyzes Oxygenation of the Antitubercular Drugs Thiacetazone and Ethionamide [J].
Francois, Asvi A. ;
Nishida, Clinton R. ;
de Montellano, Paul R. Ortiz ;
Phillips, Ian R. ;
Shephard, Elizabeth A. .
DRUG METABOLISM AND DISPOSITION, 2009, 37 (01) :178-186
[10]   Identification of novel variants of the flavin-containing monooxygenase gene family in African Americans [J].
Furnes, B ;
Feng, JN ;
Sommer, SS ;
Schlenk, D .
DRUG METABOLISM AND DISPOSITION, 2003, 31 (02) :187-193