期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：52
页码：18757-18762
DOI：10.1073/pnas.1421708111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAcetaminophen toxicity is significantly influenced by the hepatocyte circadian clock through its control of xenobiotic metabolizing systems. We have found that, although the central circadian clock can influence detoxification through glutathione biosynthesis, the autonomous hepatocyte circadian clock also controls major aspects of acetaminophen (APAP) bioactivation. One mechanism by which APAP bioactivation is controlled is through the clock's regulation of cytochrome P450-dependent activity through NADPH-cytochrome P450 oxidoreductase. 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.
