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.

Figure 1. Metabolism of sulindac by flavin-containing monooxygenase 3

The scheme depicts the enzymatic metabolism of sulindac by FMO3. Sulindac is ingested as a prodrug, sulindac sulfoxide, which exists as the R- and S-enantiomeric forms. Both forms are converted by the gut bacteria to its reduced sulfide form, which is then absorbed. It is the sulfide form that is metabolically active. The sulfide form is then inactivated in the body by FMO3 back to the sulfoxide and then to the inactive sulfone form. FMO3: Flavin-containing monooxygenase 3 gene. Adapted with permission from [54].

Figure 2. Effect of flavin-containing monooxygenase 3 gene polymorphisms on sulindac metabolism in familial adenomatous polyposis patients

The scheme depicts the sequential effect of two common polymorphisms of FMO3, E158K and E308G, on reducing polyp burden in patients with FAP being treated with sulindac [47,48]. FAP: Familial adenomatous polyposis; FMO3: Flavin-containing monooxygenase 3 gene.