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Emerging roles of xenobiotic detoxification enzymes in metabolic diseases

Michael C Petriello, Jessie B Hoffman, Andrew J Morris

    Reviews on Environmental Health
    |November 13, 2016
    PubMed

    Insights

    Detoxification enzymes like flavin-containing monooxygenase 3 (FMO3) and aryl hydrocarbon receptor (AhR) play key roles in metabolic diseases and normal physiology. Understanding these pathways reveals how environmental pollutants impact health.

    Area of Science:

    • Biochemistry
    • Metabolic disease research
    • Environmental toxicology

    Background:

    • Mammalian detoxification enzymes, such as cytochrome P450s and flavin-containing monooxygenases (FMOs), and transcriptional activators like the aryl hydrocarbon receptor (AhR), possess known roles in xenobiotic metabolism.
    • Emerging evidence indicates these pathways also have significant endogenous functions in normal physiology and the development of metabolic diseases.

    Purpose of the Study:

    • To review the endogenous roles of specific xenobiotic-metabolizing enzymes and receptors.
    • To highlight the involvement of flavin-containing monooxygenase 3 (FMO3) in trimethylamine-N-oxide (TMAO) production, a biomarker for cardiometabolic disease.
    • To discuss the aryl hydrocarbon receptor (AhR) as a sensor for endogenous ligands, including those from gut microbiota.

    Main Methods:

    • Literature review and synthesis of existing research.
    • Focus on flavin-containing monooxygenase 3 (FMO3) and aryl hydrocarbon receptor (AhR) pathways.
    • Analysis of their roles in endogenous metabolism and disease pathology.

    Main Results:

    • Flavin-containing monooxygenase 3 (FMO3) contributes to the formation of trimethylamine-N-oxide (TMAO), a biomarker linked to cardiometabolic diseases.
    • The aryl hydrocarbon receptor (AhR) functions as a sensor for endogenous molecules, notably those derived from gut microbial activity.
    • These pathways, traditionally viewed for xenobiotic detoxification, are integral to endogenous metabolic regulation.

    Conclusions:

    • Xenobiotic sensing pathways have critical endogenous roles in metabolism and disease.
    • Understanding these dual functions is essential for deciphering the impact of environmental pollutants on physiological processes.
    • Further research into these pathways may offer new insights into metabolic disease treatment and prevention.

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