Combined contributions of genetic and non-genetic factors to FMO-catalyzed drug metabolism : SNP and NO

초록

The flavin-containing monooxygenases (FMOs) constitute a family of FAD-, NADPH, and O2-dependent microsomal enzymes that catalyze the oxygenation of many nitrogen-, sulfur-, phosphorous-, selenium-, and other nucleophilic heteroatom-containing chemicals, drugs, and pesticides. In human, FMO3 is the prominent isoform in adult liver and is the gene associated with the majority of FMO-catalyzed hepatic metabolism. In addition, there is considerable inter-individual and inter-ethnic variability in the levels and activities of FMO3. This variability comes from the common or rare mutations, which are single base changes termed as allelic variants by single nucleotide polymorphism (SNP). SNP in the coding regions of FMO3 influence also the activity according to the drug substrates of varying chemical structure that correlate with each mutation on the FMO3 gene. In particular, human FMO activity and expression can be non-genetically suppressed by nitric oxide (NO), which is a reactive free radical overproduced under inflammatory conditions like liver diseases. The NO in the liver or brain can depress FMO3 activity through protein S-nitrosylation, mRNA destabilization and/or transcriptional inhibition, and cause more severe drug toxicity in vivo in patients with activity-related SNP mutations on the FMO3. Therefore, our results suggest that the substantial in vivo FMO activity can be affected genetically and non-genetically by combined factors of SNP and NO, respectively.