**7. Summary and perspectives**

The importance of chronopharmacology has been reviewed 10 years ago [16]. Circadian rhyme governs many physiological functions, and the RNA-Seq revealed that over 3000 genes in the liver showed circadian oscillation [72]. Over the past two decades, research has investigated the molecular mechanisms linking circadian clock genes with the regulation of hepatic physiological functions, using global clock-gene-knockout mice, or mice with liver-specific knockout of clock genes or clock-controlled genes. Clock dysfunction accelerates the development of liver diseases such as fatty liver diseases, cirrhosis, hepatitis, and liver cancer, and these disorders also disrupt clock function. Similarly, clock dysfunction clearly affects drug efficacy and toxicity.

**References**

cshperspect.a032516

060909-153128

2016 Apr 05

iub.1160

lism. 2009;**10**:104-115

10.1517/17425255.2011.544251

[1] Top D, Young MW. Coordination between differentially regulated circadian clocks generates rhythmic behavior. Cold Spring Harbor Perspectives in Biology. 2017;1-27.

Circadian Clock Gene Expression and Drug/Toxicant Interactions as Novel Targets…

http://dx.doi.org/10.5772/intechopen.74597

27

[2] Rosbash M.A 50-year personal journey: Location, gene expression, and circadian rhythms. Cold Spring Harbor Perspectives in Biology. 2017;**9**(12):1-12. pii: a032516. DOI: 10.1101/

[3] Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: Organization and coordination of central and peripheral clocks. Annual Review of Physiology. 2010;

[4] Richards J, Gumz ML. Mechanism of the circadian clock in physiology. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2013;**304**:

[5] Tahara Y, Shibata S. Circadian rhythms of liver physiology and disease: Experimental and clinical evidence. Nature Reviews. Gastroenterology & Hepatology. 2016;**13**(4):

[6] Buhr ED, Takahashi JS. Molecular components of the mammalian circadian clock. Handbook of Experimental Pharmacology. 2013;**217**:3-27. DOI: 10.1007/978-3-642-25950-0\_1 [7] Partch CL, Green CB, Takahashi JS. Molecular architecture of the mammalian circadian

[8] Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annual Review of Neuroscience. 2012:1445-1462. DOI: 10.1146/annurev-neuro-

[9] Takahashi JS. Molecular architecture of the circadian clock in mammals. In: Sassone-Corsi P, Christen Y, editors. A Time for Metabolism and Hormones. Cham, CH: Springer;

[10] Dallmann R, Brown SA, Gachon F. Chronopharmacology: New insights and therapeutic implications. Annual Review of Pharmacology and Toxicology. 2014;**54**:339-361. DOI:

[11] Froy O. Cytochrome P450 and the biological clock in mammals. Current Drug Metabo-

[12] Kosir R, Spaninger K, Rozman D. Circadian events in human diseases and in cytochrome P450-related drug metabolism and therapy. IUBMB Life. 2013;**65**:487-496. DOI: 10.1002/

[13] Gachon F, Firsov D. The role of circadian timing system on drug metabolism and detoxification. Expert Opinion on Drug Metabolism & Toxicology. 2011;**7**:147-158. DOI:

clock. Trends in Cell Biology. 2014;**24**(2):90-99. DOI: 10.1016/j.tcb.2013.07.002

pii: a033589. DOI: 10.1101/cshperspect.a033589

R1053-R1064. DOI: 10.1152/ajpregu.00066.2013

217-226. DOI: 10.1038/nrgastro.2016.8

10.1146/annurev-pharmtox-011613-135923

**72**:517-549. DOI: 10.1146/annurev-physiol-021909-135821

In the liver, Phase-I is composed mainly of cytochromes P450 involved in detoxification and hormone and lipid metabolism [11], which are regulated by nuclear receptors. Phase-II enzymes modify the phase-I metabolites by conjugation reactions, while phase-III includes membrane transporters responsible for the elimination of modified xenobiotics. Phases I−III of drug metabolism are under strong circadian regulation [15]. The rhythmic control of xenobiotic detoxification provides the molecular basis for the dose- and time-dependence of drug toxicities and efficacy, and makes the circadian clock gene expression as a target for chronopharmacology [10], not only for drugs but also for traditional medicines [73]. Circadian rhythms also greatly affect drug toxicity at the different times of administration [74]. Circadian rhythms are controlled, regulated and maintained by clock gene networks, which are the emerging targets of chronopharmacology and chronotoxicology.
