The international journal of biochemistry & cell biologyFeb 6, 2024

Daily cycle control of a liver enzyme involved in drug metabolism in mice

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 29, 2026

Abstract

Flavin-containing monooxygenase 3 mRNA and protein levels showed robust diurnal rhythms in mouse liver and cell lines.

Diurnal variations in flavin-containing monooxygenase 3 expression are associated with changes in drug metabolism.
In vitro studies revealed altered N-oxidation rates of procainamide corresponding to the enzyme's expression at different times.
E4 promoter-binding protein 4 negatively regulates flavin-containing monooxygenase 3 expression in liver cell lines.
Brain and muscle ARNT-like protein-1 positively influences the expression of flavin-containing monooxygenase 3.
Transcriptional regulation involves E4 promoter-binding protein 4 binding to a specific element and brain and muscle ARNT-like protein-1 activating three distinct sites.

Simplified

Circadian genes play an important role in the field of drug metabolism. Flavin-containing monooxygenase 3 is a well-known phase I enzyme which participates in metabolism of many exogenous and endogenous substances, especially production of trimethylamine N-oxide. Here, we aimed to decipher diurnal rhythms of flavin-containing monooxygenase 3 expression and activity, and explore the regulation mechanism by clock genes. Our results showed that its mRNA and protein exhibited robust diurnal rhythms in mouse liver and cell lines. Consistently, significant alterations were observed for in vitro microsomal N-oxidation rates of procainamide, which kept in line with its protein expression at different time in wild-type and reverse erythroblastosis virus α knockout mice. Further, flavin-containing monooxygenase 3 was negatively regulated by E4 promoter-binding protein 4 in AML12 and Hepa1-6 cells, while it was positively influenced by reverse erythroblastosis virus α and brain and muscle ARNT-like protein-1. Moreover, luciferase reporter assays and electrophoretic mobility shift assays showed E4 promoter-binding protein 4 inhibited the transcription of flavin-containing monooxygenase 3 by binding to a D-box1 element (-1606/-1594 bp), while brain and muscle ARNT-like protein-1 positively activated the transcription via direct binding to three E-boxes (-863/-858 bp, -507/-498 bp, and -115/-104 bp) in this enzyme promoter. Taken together, this study would be helpful to reveal the mechanism of clock-controlled drug metabolism and facilitate the practice of chrono-therapeutics.

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

Daily cycle control of a liver enzyme involved in drug metabolism in mice

Abstract

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Competing interests

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Abstract

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