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Research ArticleArticle

Circadian Expression Profiles of Drug-Processing Genes and Transcription Factors in Mouse Liver

Yu-Kun Jennifer Zhang, Ronnie L. Yeager and Curtis D. Klaassen
Drug Metabolism and Disposition January 2009, 37 (1) 106-115; DOI: https://doi.org/10.1124/dmd.108.024174
Yu-Kun Jennifer Zhang
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Ronnie L. Yeager
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Curtis D. Klaassen
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Abstract

Temporal coordination of hepatic drug-processing gene (DPG) expression facilitates absorption, biotransformation, and excretion of exogenous and endogenous compounds. To further elucidate the circadian rhythm of hepatic DPG expression, male C57BL/6 mice were subjected to a standard 12-h light/dark cycle, and livers were collected at 2:00, 6:00, and 10:00 AM and 2:00, 6:00, and 10:00 PM. The mRNAs of hepatic phase I enzymes (cytochromes P450, aldehyde dehydrogenases, and carboxylesterases), phase II enzymes (glucuronosyltransferases, sulfotransferases, and glutathione S-transferases), uptake and efflux transporters, and transcription factors were quantified. Messenger RNAs of various genes were graphed across time of day and compared by hierarchical clustering. In general, the mRNA of phase I enzymes increased during the dark phase, whereas the mRNAs of most phase II enzymes and transporters reached maximal levels during the light phase. The majority of hepatic transcription factors exhibited expression peaks either before or after the onset of the dark phase. During the same time period, the negative clock regulator gene Rev-Erbα and the hepatic clock-controlled gene Dbp also reached mRNA expression peaks. Considering their important role in xenobiotic metabolism, hepatic transcription factors, such as constitutive androstane receptor, pregnane X receptor, aryl hydrocarbon receptor, and peroxisomal proliferator activated receptor α, may be involved in coupling the hepatic circadian clock to environmental cues. Taken together, these data demonstrate that the circadian expression of the DPG battery and transcription factors contribute to the temporal detoxification cycle in the liver.

Footnotes

  • This study was supported by the National Institutes of Health [Grants ES-09649, ES-09716, ES-07079, ES-018714, and RR-021940].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.024174.

  • ABBREVIATIONS: DPG, drug-processing gene; Oatp, organic anion-transporting polypeptide; Oat, organic anion transporter; Oct, organic cation transporter; Mrp/MRP, multidrug resistance-associated protein; Bcrp/BCRP, breast cancer resistance protein; Mdr, multidrug resistance; Mate 1, multidrug and toxin extrusion 1; Atp8b1, ATPase, class I, type 8b, member 1; P450, cytochrome P450; Aldh, aldehyde dehydrogenase; Ces, carboxylesterase; Nqo, NAD(P)H:quinone oxidoreductase; Pon, paraoxonase; Ugt/UGT, UDP-glucuronosyltransferase; Sult, sulfotransferase; Gst, glutathione S-transferase; CAR, constitutive androstane receptor; PXR, pregnane X receptor; PPARα, peroxisomal proliferator-activated receptor alpha; HNF, hepatocyte nuclear factor; AhR, aryl hydrocarbon receptor; Nrf2, nuclear factor erythroid 2-related factor 2; C/EBP, CAAT/enhancer-binding protein; Dbp, albumin D site binding protein; Bmal1, brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1; bDNA, branched DNA; Keap1, Kelch-like ECH-associated protein 1; Cpr, cytochrome P450 reductase; Alas1, δ-aminolevulinic acid synthase; UDP-GA, UDP-glucuronic acid; PAPS, phosphoadenosine-5′-phosphosulfate; Papss2, PAPS synthase 2; Gclc, glutamate-cysteine ligase.

    • Received August 25, 2008.
    • Accepted October 2, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (1)
Drug Metabolism and Disposition
Vol. 37, Issue 1
1 Jan 2009
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Research ArticleArticle

Circadian Expression Profiles of Drug-Processing Genes and Transcription Factors in Mouse Liver

Yu-Kun Jennifer Zhang, Ronnie L. Yeager and Curtis D. Klaassen
Drug Metabolism and Disposition January 1, 2009, 37 (1) 106-115; DOI: https://doi.org/10.1124/dmd.108.024174

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Research ArticleArticle

Circadian Expression Profiles of Drug-Processing Genes and Transcription Factors in Mouse Liver

Yu-Kun Jennifer Zhang, Ronnie L. Yeager and Curtis D. Klaassen
Drug Metabolism and Disposition January 1, 2009, 37 (1) 106-115; DOI: https://doi.org/10.1124/dmd.108.024174
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