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Research ArticleArticle

Population Distribution of Human Flavin-Containing Monooxygenase Form 3: Gene Polymorphisms

John R. Cashman, Jun Zhang, James Leushner and Andreas Braun
Drug Metabolism and Disposition December 2001, 29 (12) 1629-1637;
John R. Cashman
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Jun Zhang
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James Leushner
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Andreas Braun
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Abstract

The N-oxygenation of amines by the human flavin-containing monooxygenase (form 3) (FMO3) represents an important means for the conversion of lipophilic nucleophilic heteroatom-containing compounds into more polar and readily excreted products. Certain mutations of the human FMO3 gene have been linked to abnormal drug or chemical metabolism. For example, abnormal N-oxygenation of trimethylamine has been shown to segregate with mutations of human FMO3. To date, however, it is not known whether there is a pharmacogenetic basis for abnormal drug metabolism by human FMO3. The objective of this study was to estimate the allele and genotype frequencies at three variable DNA sites in the FMO3 gene in male and female blood bank donors representative of non-Hispanic Caucasians, non-Hispanic African Americans, Hispanics, and Asians sampled from the United States. The common polymorphisms at variable sites 158, 257, and 308 were experimentally determined using a high-throughput chip-based genotype variation detection method combining MassEXTEND and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. We also compared the genetic variation of nonhuman primate FMO3 with the human FMO3 gene. Exon sequence analysis of the monkey FMO3 gene sequence showed that it was similar to the human gene sequence but differed from the human consensus sequence at 31 fixed positions. Compared with that of human, the chimpanzee exon sequence had one polymorphism that induced an amino acid change. The evolutionary history of theFMO3 gene was inferred from the pattern of haplotype relationships across different populations and species. Statistically significant heterogeneity in the relative frequencies of single and multiple site alleles, haplotypes, and genotypes of the humanFMO3 among ethnic subdivisions suggests that population differences in the susceptibility of humans to abnormal metabolism or adverse drug reactions for chemicals metabolized by human FMO3 could exist.

Footnotes

  • The authors acknowledge the financial support of the National Institute of Health Grants GM36426 and DK/ES59618 and the University of California Tobacco-Related Disease Research Program Grant 9RT-0196.

  • Abbreviations used are::
    FMO
    flavin-containing monooxygenases
    TMA
    trimethylamine
    MALDI-TOF
    matrix-assisted laser desorption ionization time-of-flight
    PCR
    polymerase chain reaction
    -bio
    nonbiotin-labeled primers
    MS
    mass spectrometry
    LC
    liquid chromatography
    • Received May 29, 2001.
    • Accepted August 22, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (12)
Drug Metabolism and Disposition
Vol. 29, Issue 12
1 Dec 2001
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Research ArticleArticle

Population Distribution of Human Flavin-Containing Monooxygenase Form 3: Gene Polymorphisms

John R. Cashman, Jun Zhang, James Leushner and Andreas Braun
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1629-1637;

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Research ArticleArticle

Population Distribution of Human Flavin-Containing Monooxygenase Form 3: Gene Polymorphisms

John R. Cashman, Jun Zhang, James Leushner and Andreas Braun
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1629-1637;
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