Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase

Brian P. Johnson, Jacqueline A. Walisser, Yan Liu, Anna L. Shen, Erin L. McDearmon, Susan M. Moran, Brian E. McIntosh, Aaron L. Vollrath, Andrew C. Schook, Joseph S. Takahashi, Christopher A. Bradfield

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The diurnal variation in acetaminophen (APAP) hepatotoxicity (chronotoxicity) reportedly is driven by oscillations in metabolism that are influenced by the circadian phases of feeding and fasting. To determine the relative contributions of the central clock and the hepatocyte circadian clock in modulating the chronotoxicity of APAP, we used a conditional null allele of brain and muscle Arnt-like 1 (Bmal1, aka Mop3 or Arntl) allowing deletion of the clock from hepatocytes while keeping the central and other peripheral clocks (e.g., the clocks controlling food intake) intact. We show that deletion of the hepatocyte clock dramatically reduces APAP bioactivation and toxicity in vivo and in vitro because of a reduction in NADPH-cytochrome P450 oxidoreductase gene expression, protein, and activity.

Original languageEnglish (US)
Pages (from-to)18757-18762
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number52
DOIs
StatePublished - Dec 30 2014

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Keywords

  • Acetaminophen toxicity
  • Bmal1
  • Chronotoxicity
  • Circadian clock
  • NADPH-cytochrome P450 oxidoreductase

ASJC Scopus subject areas

  • General

Cite this

Johnson, B. P., Walisser, J. A., Liu, Y., Shen, A. L., McDearmon, E. L., Moran, S. M., McIntosh, B. E., Vollrath, A. L., Schook, A. C., Takahashi, J. S., & Bradfield, C. A. (2014). Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase. Proceedings of the National Academy of Sciences of the United States of America, 111(52), 18757-18762. https://doi.org/10.1073/pnas.1421708111