Drug metabolism by flavin-containing monooxygenases of human and mouse

ABSTRACT

Introduction: Flavin-containing monooxygenases (FMOs) play an important role in drug metabolism.

Areas covered: We focus on the role of FMOs in the metabolism of drugs in human and mouse. We describe FMO genes and proteins of human and mouse; the catalytic mechanism of FMOs and their significance for drug metabolism; differences between FMOs and CYPs; factors contributing to potential underestimation of the contribution of FMOs to drug metabolism; the developmental and tissue-specific expression of FMO genes and differences between human and mouse; and factors that induce or inhibit FMOs. We discuss the contribution of FMOs of human and mouse to the metabolism of drugs and how genetic variation of FMOs affects drug metabolism. Finally, we discuss the utility of animal models for FMO-mediated drug metabolism in humans.

Expert opinion: The contribution of FMOs to drug metabolism may be underestimated. As FMOs are not readily induced or inhibited and their reactions are generally detoxifications, the design of drugs that are metabolized predominantly by FMOs offers clinical advantages. Fmo1^(-/-),Fmo2^(-/-),Fmo4^(-/-) mice provide a good animal model for FMO-mediated drug metabolism in humans. Identification of roles for FMO1 and FMO5 in endogenous metabolism has implications for drug therapy and initiates an exciting area of research.

KEYWORDS:

• Animal model
• cytochrome P450
• CYP
• drug metabolism
• flavin-containing monooxygenase
• FMO
• genetic variant
• human
• knockout mouse
• mouse

Article highlights

• FMOs are involved in the metabolism of a number of therapeutic drugs; in most cases the drugs are metabolized also by other enzymes, particularly CYPs, but some are metabolized exclusively or predominantly by FMOs

• The contribution of FMOs to drug metabolism may be underestimated, in particular, the ability of FMO1 and FMO5 to catalyze Baeyer-Villiger reactions

• Human and mouse differ with respect to the complement of FMOs present in major organs of drug metabolism, consequently, wild-type mouse is not a good model for FMO-mediated metabolism in human

• Genetic variants of FMOs, particularly of FMO2 and FMO3, affect metabolism of substrates of these enzymes

• FMO1 and FMO5 function in endogenous metabolism, which has implications for drug therapy

• Female knockout mice in which the Fmo1, Fmo2 and Fmo4 genes have been disrupted are a good model for FMO-mediated drug metabolism in human

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.