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J Pharmacol Exp Ther. 2017 Nov;363(2):265-274. doi: 10.1124/jpet.117.243113. Epub 2017 Aug 17.

Genetic and Nongenetic Factors Associated with Protein Abundance of Flavin-Containing Monooxygenase 3 in Human Liver.

Author information

1
Departments of Pharmaceutics (M.X., D.K.B., K.G.C., K.E.T., B.P.), Medicinal Chemistry (C.K.Y., A.E.R.), and Genome Sciences (D.N.), University of Washington, Seattle, Washington; Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (M.X.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.S.); Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (A.G., R.E.P., R.G., J.S.L.); and Section of Genomic Pediatrics, Department of Pediatrics, and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin (U.B.).
2
Departments of Pharmaceutics (M.X., D.K.B., K.G.C., K.E.T., B.P.), Medicinal Chemistry (C.K.Y., A.E.R.), and Genome Sciences (D.N.), University of Washington, Seattle, Washington; Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (M.X.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.S.); Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri (A.G., R.E.P., R.G., J.S.L.); and Section of Genomic Pediatrics, Department of Pediatrics, and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin (U.B.) bhagwat@uw.edu.

Abstract

Hepatic flavin-containing mono-oxygenase 3 (FMO3) metabolizes a broad array of nucleophilic heteroatom (e.g., N or S)-containing xenobiotics (e.g., amphetamine, sulindac, benzydamine, ranitidine, tamoxifen, nicotine, and ethionamide), as well as endogenous compounds (e.g., catecholamine and trimethylamine). To predict the effect of genetic and nongenetic factors on the hepatic metabolism of FMO3 substrates, we quantified FMO3 protein abundance in human liver microsomes (HLMs; n = 445) by liquid chromatography-tandem mass chromatography proteomics. Genotyping/gene resequencing, mRNA expression, and functional activity (with benzydamine as probe substrate) of FMO3 were also evaluated. FMO3 abundance increased 2.2-fold (13.0 ± 11.4 pmol/mg protein vs. 28.0 ± 11.8 pmol/mg protein) from neonates to adults. After 6 years of age, no significant difference in FMO3 abundance was found between children and adults. Female donors exhibited modestly higher mRNA fragments per kilobase per million reads values (139.9 ± 76.9 vs. 105.1 ± 73.1; P < 0.001) and protein FMO3 abundance (26.7 ± 12.0 pmol/mg protein vs. 24.1 ± 12.1 pmol/mg protein; P < 0.05) compared with males. Six single nucleotide polymorphisms (SNPs), including rs2064074, rs28363536, rs2266782 (E158K), rs909530 (N285N), rs2266780 (E308G), and rs909531, were associated with significantly decreased protein abundance. FMO3 abundance in individuals homozygous and heterozygous for haplotype 3 (H3), representing variant alleles for all these SNPs (except rs2066534), were 50.8% (P < 0.001) and 79.5% (P < 0.01), respectively, of those with the reference homozygous haplotype (H1, representing wild-type). In summary, FMO3 protein abundance is significantly associated with age, gender, and genotype. These data are important in predicting FMO3-mediated heteroatom-oxidation of xenobiotics and endogenous biomolecules in the human liver.

PMID:
28819071
PMCID:
PMC5697103
DOI:
10.1124/jpet.117.243113
[Indexed for MEDLINE]
Free PMC Article

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