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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Genetic Variability at the Human FMO1 Locus: Significance of a Basal Promoter Yin Yang 1 Element Polymorphism (FMO1^*6)

Department of Pediatrics, Birth Defects Research Center and Department of Pharmacology/Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

The flavin-containing monooxygenases (FMOs) are important for the disposition of a variety of toxicants, therapeutics, and dietary components. Although FMO1 is the dominant isoform in fetal liver and adult kidney and intestine and despite up to a 10-fold intersubject variation in expression, a paucity of information is available on FMO1 genetic variability. To address this issue, 24 samples from the Coriell DNA Polymorphism Discovery Resource Panel were sequenced revealing 10 common single nucleotide polymorphisms (SNPs): four located upstream of the structural gene; three within exonic sequences; one within the intron 1 splice donor site; and two with the 3'-untranslated region. Six of these variants are novel. Compared with other FMO loci within the chromosome 1q23-25 cluster, FMO1 seems more highly conserved. Of the identified FMO1 SNPs, only a C>A transversion 9,536 base pairs upstream of the exon 2 ATG start codon (g.-9,536C>A) would likely affect function, because it lies within the conserved core binding sequence for the yin yang 1 (YY1) transcription factor. Electrophoretic mobility shift assays demonstrated that the g.-9,536C>A transversion eliminated YY1 binding. Furthermore, data from transient expression assays in HepG2 cells suggested this SNP could account for a 2- to 3-fold loss of FMO1 promoter activity. Genotype analysis revealed a g.-9,536A allele (FMO1^*6) frequency of 13 and 11% in African- and northern European-Americans, respectively, but a significantly higher frequency of 30% in Hispanic-Americans. Thus, the FMO1^*6 variant may account for some of the observed interindividual variation in FMO1 expression.

Address correspondence to: Dr. Ronald N. Hines, Department of Pediatrics, Birth Defects Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee WI 53226-4801. E-mail: rhines{at}mail.mcw.edu

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