1. Academic Validation
  2. Bmal1 regulates circadian expression of cytochrome P450 3a11 and drug metabolism in mice

Bmal1 regulates circadian expression of cytochrome P450 3a11 and drug metabolism in mice

  • Commun Biol. 2019 Oct 16;2:378. doi: 10.1038/s42003-019-0607-z.
Yanke Lin  # 1 Shuai Wang  # 1 2 Ziyue Zhou 1 Lianxia Guo 1 Fangjun Yu 1 Baojian Wu 1
Affiliations

Affiliations

  • 1 1Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, 510632 Guangzhou, China.
  • 2 2Integrated Chinese and Western Medicine Postdoctoral research station, Jinan University, 601 Huangpu Avenue West, Guangzhou, China.
  • # Contributed equally.
Abstract

Metabolism is a major defense mechanism of the body against xenobiotic threats. Here we unravel a critical role of Bmal1 for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal1 deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Cell-based experiments confirm that Dbp and Hnf4α activate Cyp3a11 transcription by their binding to a D-box and a DR1 element in the Cyp3a11 promoter, respectively. Bmal1 binds to the P1 distal promoter to regulate Hnf4α transcriptionally. Cellular regulation of Cyp3a11 by Bmal1 is Dbp- and Hnf4α-dependent. Bmal1 deficiency sensitizes mice to toxicities of drugs such as aconitine and triptolide (and blunts circadian toxicity rhythmicities) due to elevated drug exposure. In summary, Bmal1 connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time.

Keywords

Biochemistry; Cell biology; Molecular biology; Toxicology.

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