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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants

Sevasti B. Koukouritaki, Mark T. Poch, Marilyn C. Henderson, Lisbeth K. Siddens, Sharon K. Krueger, Jonathan E. VanDyke, David E. Williams, Nicholas M. Pajewski, Tao Wang and Ronald N. Hines
Journal of Pharmacology and Experimental Therapeutics January 2007, 320 (1) 266-273; DOI: https://doi.org/10.1124/jpet.106.112268
Sevasti B. Koukouritaki
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Mark T. Poch
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Marilyn C. Henderson
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Lisbeth K. Siddens
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Sharon K. Krueger
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Jonathan E. VanDyke
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David E. Williams
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Nicholas M. Pajewski
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Tao Wang
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Ronald N. Hines
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Abstract

Flavin-containing monooxygenases (FMOs) are important for the disposition of many therapeutics, environmental toxicants, and nutrients. FMO3, the major adult hepatic FMO enzyme, exhibits significant interindividual variation. Eighteen FMO3 single-nucleotide polymorphism (SNP) frequencies were determined in 202 Hispanics (Mexican descent), 201 African Americans, and 200 non-Latino whites. Using expressed recombinant enzyme with methimazole, trimethylamine, sulindac, and ethylenethiourea, the novel structural variants FMO3 E24D and K416N were shown to cause modest changes in catalytic efficiency, whereas a third novel variant, FMO3 N61K, was essentially devoid of activity. The latter variant was present at an allelic frequency of 5.2% in non-Latino whites and 3.5% in African Americans, but it was absent in Hispanics. Inferring haplotypes using PHASE, version 2.1, the greatest haplotype diversity was observed in African Americans followed by non-Latino whites and Hispanics. Haplotype 2A and 2B, consisting of a hypermorphic promoter SNP cluster (-2650C>G, -2543T>A, and -2177G>C) in linkage with synonymous structural variants was inferred at a frequency of 27% in the Hispanic population, but only 5% in non-Latino whites and African Americans. This same promoter SNP cluster in linkage with one or more hypomorphic structural variant also was inferred in multiple haplotypes at a total frequency of 5.6% in the African-American study group but less than 1% in the other two groups. The sum frequencies of the hypomorphic haplotypes H3 [15,167G>A (E158K)], H5B [-2650C>G, 15,167G>A (E158K), 21,375C>T (N285N), 21,443A>G (E308G)], and H6 [15,167G>A (E158K), 21,375C>T (N285N)] was 28% in Hispanics, 23% in non-Latino whites, and 24% in African Americans.

Footnotes

  • This study was supported in part by Public Health Service Grants CA53106 (to R.N.H.) and HL38650 (to D.E.W.) and with funds from the Children's Research Institute, Children Hospital and Health Systems.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.112268.

  • ABBREVIATIONS: FMO, flavin-containing monooxygenase; SNP, single-nucleotide polymorphism; SBE, single base extension; Sf, Spodoptera frugiperda; AMOVA, analysis of molecular variance; ANOVA, analysis of variance; Kcat, catalytic rate constant; Km, Michaelis-Menten constant.

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received August 9, 2006.
    • Accepted October 17, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants

Sevasti B. Koukouritaki, Mark T. Poch, Marilyn C. Henderson, Lisbeth K. Siddens, Sharon K. Krueger, Jonathan E. VanDyke, David E. Williams, Nicholas M. Pajewski, Tao Wang and Ronald N. Hines
Journal of Pharmacology and Experimental Therapeutics January 1, 2007, 320 (1) 266-273; DOI: https://doi.org/10.1124/jpet.106.112268

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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants

Sevasti B. Koukouritaki, Mark T. Poch, Marilyn C. Henderson, Lisbeth K. Siddens, Sharon K. Krueger, Jonathan E. VanDyke, David E. Williams, Nicholas M. Pajewski, Tao Wang and Ronald N. Hines
Journal of Pharmacology and Experimental Therapeutics January 1, 2007, 320 (1) 266-273; DOI: https://doi.org/10.1124/jpet.106.112268
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