Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Abstract

Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases. Keywords chemoprevention; familial adenomatous polyposis; flavin-containing monooxygenase 3; gastrointestinal diseases; SNP; sulindac sulfide; trimethylaminuria Humans metabolize a vast array of endogenous and exogenous compounds, including drugs and xenobiotics. It has been observed that different individuals, genders and ethnicities respond differently to the same compounds. This has been attributed to multiple factors, one of which is SNPs. With the completion of the human genome sequence and the discovery of existing SNPs in the genome, interest has focused on the role of genetic polymorphisms of enzymeencoding genes involved in the metabolism of both endogenous and exogenous substances.The flavin-containing monooxygenases (FMOs) belong to a family of flavoprotein enzymes that catalyze the oxidation of a broad array of nucleophilic heteroatom-containing drugs, pesticides and chemicals [1][2][3][4]. There are six human isoforms of flavin-containing monooxygenases, of which five are functional. An additional gene cluster containing five pseudogenes has also been identified in both the human and mouse genome [5][6][7][8][9][10].

New Aspects on the Metabolic role of Intestinal Microbiota in the Development of Atherosclerosis

“…adefovir and tenofovir), a category of antiviral agents, can also inhibit FMO3 activity [54]. FMO3 has been reported to have various genetic polymorphisms which lead to different levels of functionality [55]. Studies on trimethylaminuria, a genetic disorder of FMO3 inadequacy, have been the driving force for the discovery of many of these polymorphisms.…”

Effects of Single-Nucleotide Polymorphisms of FMO3 and FMO6 Genes on Pharmacokinetic Characteristics of Sulindac Sulfide in Premature Labor

“…Sulindac is also oxidized to an inactive metabolite, sulindac sulfone. The sulfide form is inactivated by flavin-containing mono-oxygenase 3 (FMO3), and the (S)-and (R)-sulindac sulfoxides are also oxidized to sulindac sulfone by FMO3 (Hamman et al, 2000;Hisamuddin and Yang, 2007).…”

“…It has been reported that flavin-containing mono-oxygenase 6 (FMO6) has significant sequence homology with FMO3 Hernandez et al, 2004;Hisamuddin and Yang, 2007). However, unlike FMO3, the study of the effects of FMO6 polymorphisms on drug therapy has been rarely conducted.…”

“…Sulindac is also oxidized to an inactive metabolite, sulindac sulfone. The sulfide form is inactivated by flavin-containing mono-oxygenase 3 (FMO3), and the (S)-and (R)-sulindac sulfoxides are also oxidized to sulindac sulfone by FMO3 (Hamman et al, 2000;Hisamuddin and Yang, 2007).Several studies showed that FMO3 gene polymorphisms could result in interindividual and interethnic differences in FMO3 activity (Cashman and Zhang, 2002;Hernandez et al, 2003). The polymorphisms could result in differences in the pharmacokinetics and responses of drugs that are metabolized by FMO3, including sulindac.…”

“…The studied end points were pharmacodynamic responses such as polyposis prevention and regression (Hisamuddin et al, 2004(Hisamuddin et al, , 2005. However, there has been no study conducted on the effects of FMO3 genotypes on the blood concentrations of an active sulindac metabolite in clinical settings.It has been reported that flavin-containing mono-oxygenase 6 (FMO6) has significant sequence homology with FMO3 Hernandez et al, 2004;Hisamuddin and Yang, 2007). However, unlike FMO3, the study of the effects of FMO6 polymorphisms on drug therapy has been rarely conducted.…”