PT  - JOURNAL ARTICLE
AU  - Sevasti B. Koukouritaki
AU  - Mark T. Poch
AU  - Marilyn C. Henderson
AU  - Lisbeth K. Siddens
AU  - Sharon K. Krueger
AU  - Jonathan E. VanDyke
AU  - David E. Williams
AU  - Nicholas M. Pajewski
AU  - Tao Wang
AU  - Ronald N. Hines
TI  - Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants
AID  - 10.1124/jpet.106.112268
DP  - 2007 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 266--273
VI  - 320
IP  - 1
4099  - http://jpet.aspetjournals.org/content/320/1/266.short
4100  - http://jpet.aspetjournals.org/content/320/1/266.full
SO  - J Pharmacol Exp Ther2007 Jan 01; 320
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics