Title

The hepatic circadian clock modulates xenobiotic metabolism in mice

UMMS Affiliation

Department of Neurobiology; Weaver Lab

Date

8-1-2014

Document Type

Article

Medical Subject Headings

Acetaminophen; Animals; Circadian Clocks; Circadian Rhythm; Gene Expression; Liver; Male; Mice; Mice, Inbred C57BL; Pentobarbital; Periodicity; Xenobiotics

Disciplines

Neuroscience and Neurobiology

Abstract

The circadian clock generates daily cycles of gene expression that regulate physiological processes. The liver plays an important role in xenobiotic metabolism and also has been shown to possess its own cell-based clock. The liver clock is synchronized by the master clock in the brain, and a portion of rhythmic gene expression can be driven by behavior of the organism as a whole even when the hepatic clock is suppressed. So far, however, there is relatively little evidence indicating whether the liver clock is functionally important in modulating xenobiotic metabolism. Thus, mice lacking circadian clock function in the whole body or specifically in liver were challenged with pentobarbital and acetaminophen, and pentobarbital sleep time (PBST) and acetaminophen toxicity, respectively, was assessed at different times of day in mutant and control mice. The results suggest that the liver clock is essential for rhythmic changes in xenobiotic detoxification. Surprisingly, it seems that the way in which the clock is disrupted determines the rate of xenobiotic metabolism in the liver. CLOCK-deficient mice are remarkably resistant to acetaminophen and exhibit a longer PBST, while PERIOD-deficient mice have a short PBST. These results indicate an essential role of the tissue-intrinsic peripheral circadian oscillator in the liver in regulating xenobiotic metabolism.

Rights and Permissions

Citation: J Biol Rhythms. 2014 Aug;29(4):277-87. doi: 10.1177/0748730414544740. Link to article on publisher's website

Related Resources

Link to article in PubMed

PubMed ID

25238856