PT  - JOURNAL ARTICLE
AU  - Meijuan Xu
AU  - Deepak Kumar Bhatt
AU  - Catherine K. Yeung
AU  - Katrina G. Claw
AU  - Amarjit S. Chaudhry
AU  - Andrea Gaedigk
AU  - Robin E. Pearce
AU  - Ulrich Broeckel
AU  - Roger Gaedigk
AU  - Deborah A. Nickerson
AU  - Erin Schuetz
AU  - Allan E. Rettie
AU  - J. Steven Leeder
AU  - Kenneth E. Thummel
AU  - Bhagwat Prasad
TI  - Genetic and Nongenetic Factors Associated with Protein Abundance of Flavin-Containing Monooxygenase 3 in Human Liver
AID  - 10.1124/jpet.117.243113
DP  - 2017 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 265--274
VI  - 363
IP  - 2
4099  - http://jpet.aspetjournals.org/content/363/2/265.short
4100  - http://jpet.aspetjournals.org/content/363/2/265.full
SO  - J Pharmacol Exp Ther2017 Nov 01; 363
AB  - 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.