title: Aryl hydrocarbon receptor-mediated Cyp1a1 expression is modulated in a CLOCK-dependent circadian manner.
abstract: The expression of genes involved in xenobiotic detoxification is under the control of the circadian clock. The aryl hydrocarbon receptor (AhR) is one of the transcription factors responsible for the induction of detoxification enzymes in response to xenobiotic toxins, and the expression of AhR has been suggested to be regulated by a circadian oscillator. In this study, we investigated whether toxin-mediated activation of the AhR signaling pathway was modulated by CLOCK protein, a key component of the mammalian circadian clock. The expression of AhR and its DNA binding ability in the lungs of wild-type mice showed significant 24-h oscillation. Clock mutant (Clk/Clk) mice, producing CLOCK protein deficient in transcriptional activity, failed to show significant oscillation in the expression of AhR. The mRNA levels of AhR in the lungs of Clk/Clk mice were significantly lower than in wild-type mice. A single intraperitoneal injection of benzo[α]pyrene, a ligand of AhR, induced the expression of Cyp1a1 in the lungs of wild-type mice, but the induction varied depending on the benzo[α]pyrene injection time. The dosing time-dependency of benzo[α]pyrene-induced Cyp1a1 expression was also modulated by Clock gene mutation. These findings suggest that CLOCK protein affects the toxin-induced expression of detoxification enzymes through modulating the activity of AhR. Our present findings provide a molecular link between the circadian clock and xenobiotic detoxification.
authors: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Naomi
authors: N
authors: Tanimura
authors: Naoki
authors: N
authors: Kusunose
authors: Naoya
authors: N
authors: Matsunaga
authors: Satoru
authors: S
authors: Koyanagi
authors: Shigehiro
authors: S
authors: Ohdo
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000633:toxicity*; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects* / Q000235:genetics; D004334:Drug Administration Schedule; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015262:Xenobiotics / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D015262:Xenobiotics; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D056926:CLOCK Proteins; C538944:Clock protein, mouse