Genetic polymorphisms of flavin-containing monooxygenase (FMO).
Mammalian flavin-containing monooxygenase (FMO) exists as six gene families and metabolizes a plethora of drugs and xenobiotics. The major FMO in adult human liver, FMO3, is responsible for trimethylamine (TMA) N-oxygenation. A number of FMO3 mutant alleles have been described and associated with a disease termed trimethylaminuria (TMAU). The TMAU patient excretes large amounts of TMA in urine and sweat. A more recent ethnically related polymorphism in expression of the major FMO in lung, FMO2, has been described. All Caucasians and Asians genotyped to date are homozygous for a CAG --> TAG amber mutation resulting in a premature stop codon and a nonfunctional protein truncated at AA 472 (wildtype FMO2 is 535 AA). This allele has been designated hFMO2*2A. Twenty-six percent of individuals of African descent and 5% of Hispanics genotyped to date carry at least one allele coding for full-length FMO2 (hFMO2*1 allele). Preliminary evidence indicates that FMO2.1 is very active toward the S-oxygenation of low MW thioureas, including the lung toxicant ethylene thiourea. Polymorphic expression of functional FMO2 in the individuals of African and Hispanic descent may markedly influence drug metabolism and/or xenobiotic toxicity in the lung.
Krueger
Sharon K
SK
Department of Environmental and Molecular Toxicology and The Linus Pauling Institute, Oregon State University, Corvallis, USA.
Williams
David E
DE
Yueh
Mei-Fei
MF
Martin
Sarah R
SR
Hines
Ronald N
RN
Raucy
Judy L
JL
Dolphin
Colin T
CT
Shephard
Elizabeth A
EA
Phillips
Ian R
IR
D000818:Animals; D001483:Base Sequence; D005006:Ethnicity / Q000235:genetics; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008744:Methylamines / Q000378:metabolism; D008969:Molecular Sequence Data; D005810:Multigene Family; D010105:Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic; D015262:Xenobiotics / Q000378:metabolism
D007527:Isoenzymes; D008744:Methylamines; D015262:Xenobiotics; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine