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

doi:10.1073/pnas.1421708111

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 journal › Article › peer-review

70 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 language	English (US)
Pages (from-to)	18757-18762
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	52
DOIs	https://doi.org/10.1073/pnas.1421708111
State	Published - Dec 30 2014

Keywords

Acetaminophen toxicity
Bmal1
Chronotoxicity
Circadian clock
NADPH-cytochrome P450 oxidoreductase

ASJC Scopus subject areas

General

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10.1073/pnas.1421708111

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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

Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase. / Johnson, Brian P.; Walisser, Jacqueline A.; Liu, Yan et al.
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 journal › Article › peer-review

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

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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.",

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AU - McDearmon, Erin L.

AU - Moran, Susan M.

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AU - Bradfield, Christopher A.

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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.

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

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Keywords

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