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

33 Citations (Scopus)

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

Fingerprint

NADPH-Ferrihemoprotein Reductase
Circadian Clocks
Acetaminophen
Hepatocytes
Fasting
Eating
Alleles
Gene Expression
Muscles
Brain
Proteins

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase. / Johnson, Brian P.; Walisser, Jacqueline A.; Liu, Yan; Shen, Anna L.; McDearmon, Erin L.; Moran, Susan M.; McIntosh, Brian E.; Vollrath, Aaron L.; Schook, Andrew C.; Takahashi, Joseph S.; Bradfield, Christopher A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 52, 30.12.2014, p. 18757-18762.

Research output: Contribution to journalArticle

Johnson, BP, Walisser, JA, Liu, Y, Shen, AL, McDearmon, EL, Moran, SM, McIntosh, BE, Vollrath, AL, Schook, AC, Takahashi, JS & Bradfield, CA 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, vol. 111, no. 52, pp. 18757-18762. https://doi.org/10.1073/pnas.1421708111
Johnson, Brian P. ; Walisser, Jacqueline A. ; Liu, Yan ; Shen, Anna L. ; McDearmon, Erin L. ; Moran, Susan M. ; McIntosh, Brian E. ; Vollrath, Aaron L. ; Schook, Andrew C. ; Takahashi, Joseph S. ; Bradfield, Christopher A. / Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 52. pp. 18757-18762.
@article{17265fee3e1c492cbd83eb132cf916db,
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.",
keywords = "Acetaminophen toxicity, Bmal1, Chronotoxicity, Circadian clock, NADPH-cytochrome P450 oxidoreductase",
author = "Johnson, {Brian P.} and Walisser, {Jacqueline A.} and Yan Liu and Shen, {Anna L.} and McDearmon, {Erin L.} and Moran, {Susan M.} and McIntosh, {Brian E.} and Vollrath, {Aaron L.} and Schook, {Andrew C.} and Takahashi, {Joseph S.} and Bradfield, {Christopher A.}",
year = "2014",
month = "12",
day = "30",
doi = "10.1073/pnas.1421708111",
language = "English (US)",
volume = "111",
pages = "18757--18762",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "52",

}

TY - JOUR

T1 - Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase

AU - Johnson, Brian P.

AU - Walisser, Jacqueline A.

AU - Liu, Yan

AU - Shen, Anna L.

AU - McDearmon, Erin L.

AU - Moran, Susan M.

AU - McIntosh, Brian E.

AU - Vollrath, Aaron L.

AU - Schook, Andrew C.

AU - Takahashi, Joseph S.

AU - Bradfield, Christopher A.

PY - 2014/12/30

Y1 - 2014/12/30

N2 - 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.

AB - 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.

KW - Acetaminophen toxicity

KW - Bmal1

KW - Chronotoxicity

KW - Circadian clock

KW - NADPH-cytochrome P450 oxidoreductase

UR - http://www.scopus.com/inward/record.url?scp=84907585930&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907585930&partnerID=8YFLogxK

U2 - 10.1073/pnas.1421708111

DO - 10.1073/pnas.1421708111

M3 - Article

VL - 111

SP - 18757

EP - 18762

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 52

ER -