title: Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase.
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.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53792;
authors.forename: Brian P
authors.initials: BP
authors.lastname: Johnson
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53792;
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Walisser
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53792;
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53792;
authors.forename: Anna L
authors.initials: AL
authors.lastname: Shen
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208; and.
authors.forename: Erin L
authors.initials: EL
authors.lastname: McDearmon
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53792;
authors.forename: Susan M
authors.initials: SM
authors.lastname: Moran
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53792;
authors.forename: Brian E
authors.initials: BE
authors.lastname: McIntosh
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53792;
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Vollrath
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208; and.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Schook
authors.affiliation: Department of Neuroscience and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 Joseph.Takahashi@UTSouthwestern.edu bradfield@oncology.wisc.edu.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53792; Joseph.Takahashi@UTSouthwestern.edu bradfield@oncology.wisc.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bradfield
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D002940:Circadian Rhythm; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D018712:Analgesics, Non-Narcotic; D056925:Circadian Rhythm Signaling Peptides and Proteins; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System
keywords: Bmal1; NADPH-cytochrome P450 oxidoreductase; acetaminophen toxicity; chronotoxicity; circadian clock