The Autonomous Hepatocyte Clock Controls Acetaminophen Bioactivation and Chronotoxicity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE34444 | GEO | 2013/08/30
SECONDARY ACCESSION(S): PRJNA149611
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-08-30 | E-GEOD-34444 | biostudies-arrayexpress
Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms, possibly through transcriptional regulation of cytochrome p450-oxidoreductase (Por). 10-20 week old Mop3fxfx mice positive or negative for Cre-recombinase driven by the albumin promoter, housed in 12 hour light:12 dark, ad lib feeding and drinking conditions were sacrificed every four hours over two separte days beginning at ZT0. A two color, reference design experiment in which kidney RNA from at least 3 mice per timepoint were pooled and labeled with Cy3 and hybridized according to Agilent protocols against a reference pool of RNA madeup from respective tissue taken from 10 week Mop3fxfx and Mop3fxfxCreAlb mice which was labeled with Cy5.
2013-08-30 | E-GEOD-34443 | biostudies-arrayexpress
Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms. 10-20 week old Mop3fxfx mice positive or negative for Cre-recombinase driven by the albumin promoter, housed in 12 hour light:12 dark, ad lib feeding and drinking conditions were sacrificed every four hours over two separte days beginning at ZT0. A two color, reference design experiment in which liver RNA from at least 3 mice per timepoint were pooled and labeled with Cy3 and hybridized according to Agilent protocols against a reference pool of RNA madeup from respective tissue taken from 10 week Mop3fxfx and Mop3fxfxCreAlb mice which was labeled with Cy5.
2013-08-30 | E-GEOD-34442 | biostudies-arrayexpress
Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms.
2013-08-30 | GSE34442 | GEO
Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms, possibly through transcriptional regulation of cytochrome p450-oxidoreductase (Por).
2013-08-30 | GSE34443 | GEO
Project description: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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