Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 52, Pages 18757-18762Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1421708111
Keywords
circadian clock; acetaminophen toxicity; NADPH-cytochrome P450 oxidoreductase; chronotoxicity; Bmal1
Categories
Funding
- National Institutes of Health [R37-ES005703, P30-CA014520, T32-CA009135, T32-ES007015]
- Howard Hughes Medical Institute
- Natural Sciences and Engineering Research Council of Canada
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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.
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