Ethnic differences in human flavin-containing monooxygenase 2 (FMO2) polymorphisms: detection of expressed protein in African-Americans.
The flavin-containing monooxygenases (FMOs) are a family of xenobiotic-metabolizing enzymes that are expressed in a species- and tissue-specific manner. FMO2 expression has been observed in pulmonary tissue from several species, but not human. Two human FMO2 point mutations have been reported: a cytosine to thymidine transition at position 1414 resulting in a premature stop codon and a thymidine insertion at position 1589 resulting in a frameshift. To define the frequency of these sequence variations and explore their significance, unrelated African-American, Caucasian, and Korean individuals were genotyped. In the African-American population tested (n = 180), the 1414C allele occurred at a 13% frequency; however, all of the tested Caucasians (n = 52) and Koreans (n = 100) were homozygous for the 1414T allele. The T1589 allele occurred at frequencies of 6.9 and 13.0% in African-Americans (n = 175) and Caucasians (n = 23), respectively, and appears to segregate with the 1414T allele. Thus, it would have no further impact on FMO2 activity. Western blot analysis of pulmonary microsomes failed to detect immunoreactive protein in 1414T homozygotes. A heterozygotic individual did exhibit a single band of the expected size, but no detectable FMO activity in the corresponding lung microsomes. Sequence analysis, however, was consistent with the 1414C allele encoding an active FMO2 enzyme. FMO2 mRNA expression was observed in most individuals, but failed to correlate with genotype or protein expression. In summary, functional FMO2 is expressed in only a small percentage of the overall population. However, in certain ethnic groups, active pulmonary FMO2 enzyme will be present in a significant number of individuals.
Whetstine
J R
JR
Departments of Pharmacology and Clinical Pharmacology, Wayne State University, Detroit, Michigan, USA.
Yueh
M F
MF
McCarver
D G
DG
Williams
D E
DE
Park
C S
CS
Kang
J H
JH
Cha
Y N
YN
Dolphin
C T
CT
Shephard
E A
EA
Phillips
I R
IR
Hines
R N
RN
D000483:Alleles; D044383:Black People / Q000235:genetics*; D015153:Blotting, Western; D005838:Genotype; D006801:Humans; D009841:Oligonucleotides / Q000032:analysis / Q000235:genetics; D010105:Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014481:United States; D001741:Black or African American
D009841:Oligonucleotides; D012333:RNA, Messenger; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)