Circadian clock gene expression as novel targets in toxicology.
Abstract
Circadian rhythms are driven and maintained by circadian clock gene networks in both brain and peripheral organs. In the liver, circadian rhythms produce oscillation in drug Phase-I, Phase-II, and Phase-III (transporters) metabolism genes, which in turn would affect drug disposition and detoxication, resulting in diurnal variations of efficacy and toxicity when drugs are given at different times of the day. On the other hand, drugs and toxicants could affect circadian clock gene expression to produce biological effects leading to therapeutic or toxic outcomes. This chapter reviewed the relevant literature and a dozen of publications from our work, discussed the interactions of circadian clock genes with drugs and/or toxicants to better understand the importance of circadian clock gene expression as novel targets in Pharmacology and Toxicology.
Keywords
- circadian clock gene expression
- liver
- drug metabolism oscillation
- chronopharmacology
- chronotoxicology
- brain
1. Introduction
Organisms on earth developed the ability to predict and restrict their activity to the night or day by endogenous circadian clock [1, 2]. The mammalian circadian clock system is timed to a 24-h solar time period and maintains rhythmic physiology. In mammals, the circadian clock influences nearly all aspects of physiology and behavior, including sleep-wake cycles, cardiovascular activity, endocrine function, body temperature, kidney function, physiology of the gastrointestinal tract, hepatic metabolism, immune function, detoxification, and the reproductive system [3, 4]. Disruption of biological rhythms produces negative effects in the short and long terms leading to various diseases [4]. For example, clock dysfunction accelerates the development of liver diseases such as fatty liver diseases, hepatitis, cirrhosis, and liver cancer. Liver disorders also, in turn, disrupt circadian clock function [5].
Circadian oscillations are generated by a set of genes forming a transcriptional autoregulatory feedback loop. In mammals, these include the core clock regulators (Clock, Bmal1, and Npsa2), the clock feedback loop regulator genes (Per1, Per2, Per3, Cry1, and Cry2), and the clock target genes (DBP, Rev-erbα (Nr1d1), RORα, Tef, CK1δ, etc.) [6, 7]. The central clock is located in the suprachiasmatic nucleus in the hypothalamus and peripheral clocks in all tissues. Peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes controlling the absorption and metabolism of xenobiotics [8]. Over the past three decades, researchers have investigated the molecular mechanisms using global clock-gene knockout mice, or clock gene mutant mice, or other genetic and molecular biology tools to elucidate molecular architecture of circadian clock in mammals [9].
Chronopharmacology and chronotoxicology is a new interdisciplinary science aimed at studying the influence of circadian system on drug disposition, efficacy, and toxicity. Xenobiotics absorption, distribution, metabolism, especially by P450, and excretion [10, 11, 12, 13, 14], all under circadian regulation. Circadian variations on these hepatic drug processing genes [15] greatly influence therapeutic effects and toxicity of drugs [10, 16, 17, 18]. The chronotherapy of anticancer drugs gives an excellent example [18]. This chapter will focus on the general aspects of circadian rhythms on drug/toxicant disposition and biological effects, and will also discuss the effects of drugs/toxicants on circadian clock gene expression as a novel target of chronopharmacology and chronotoxicology. A dozen of our publications in recent 5 years were also included for discussion.
2. Circadian rhythms affect Phase-I, Phase-II, and transporter gene expressions in the liver
Liver is the major site of xenobiotics metabolism and disposition. Accumulating evidence clearly indicates that circadian rhythms affect the gene/protein expression encoding xenobiotics uptake (Oatps and Ntcp), Phase-I metabolism (P450) and detoxication (Nrf2, MT-1, and GSH systems), Phase-II conjugation (glutathione S-transferases, UDP-glucuronosyltransferases, and sulfotransferases), and efflux transporters (Mrps and MDR) (Figure 1).
In the liver, circadian rhythm serves to synchronize the metabolism of bile acid, glucose, and lipid, and their disruption could lead to diseases and affect chronotherapy [26]. Indeed, the liver is the key organ to maintain energy metabolism which is greatly influenced by feeding, diets, and diurnal variation [5]. For example, Peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) stimulates the expression of clock genes, notably Bmal1 (also called Arntl) and Rev-erbα (also called Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Mice lacking PGC-1α show abnormal diurnal rhythms of activity, body temperature and metabolic rate [27]. Circadian clocks regulate metabolic processes not only by simply in response to daily environmental/behavioral influences but also by synchronizing the cell with its environment to modulate a host of metabolic processes [27, 28, 29].
Diurnal variation of hepatic Phase-I, Phase-II, Phase-III, and the nuclear transcription factors would affect the xenobiotic metabolism when administered at the different times of the day to impact their efficacy and toxicity, the time really matters [15].
3. Circadian rhythm disruption affects therapeutic effects and toxicity of xenobiotics in the liver
Table 1 gives a few examples of how the disruption of circadian clock could affect drug effect and toxicity. Most of the examples used genetic models with disruption of circadian clock genes or administration of drugs at different times.
Drug/toxicant | Animal models | Chronotoxicology | References |
---|---|---|---|
Carbon tetrachloride | SD rats | 18:00 toxicity >6:00, with lowest GSH levels | [36] |
Carbon tetrachloride | Per2−/− mice | Acute toxicity increased in Per2−/− mice | [37] |
Carbon tetrachloride | Per2−/− mice | Chronic toxicity, fibrosis increased in Per2−/− mice | [38] |
Acetaminophen | KM mice | 18:00 toxicity >6:00 | [23] |
Acetaminophen | Per2−/− mice | Toxicity decreased in Per2−/− mice | [40] |
Acetaminophen | Clock−/− mice | Toxicity decreased in Per2−/− mice, with prolonged PBST | [41] |
Acetaminophen | Bmal1fx/fxCreAlb mice | Reduced toxicity, reduced protein adducts, altered APAP metabolism | [42] |
Dixon (TCDD) | Per1Idc,Per2Idc mice, cells | Increased TCDD induction of Cyp1a1, Cyp1b1 | [43] |
Dixon (TCDD) | Per1Idc,Per2Idc, Per1/Per2Idc mice | Abolished diurnal variation of TCDD induction of Cyp1a1 | [44] |
Benzo[a]pyrene | Clock mutant (Clk/Clk) mice | Abolished diurnal variation of B[a]P induction of Cyp1a1 | [45] |
Bile duct ligation | Per2−/− mice | Increased BDL-induced liver injury and fibrosis | [46] |
Cholestyramine diet restricted feeding | Per1−/−/Per2−/− mice | Lost diurnal variation in bile acid metabolic enzyme genes | [47] |
Isoniazide | Swiss mice | Isoniazid hepatotoxicity at ZT1 > ZT9, ZT17 | [48] |
Chlorozoxazone | Wistar rats | Diurnal variation in CYP2E1 affect its half-life | [49] |
Alcohol | Per1−/−, Per2−/− mice | Less susceptible to alcohol toxicity | [50] |
Diethylnitrosamine (DEN) | Clockmut mouse hepatocytes | Decreased DEN metabolism and apoptosis tolerance | [51] |
Cadmium | ICR mice | Toxicity at ZT 8 > ZT 20, corresponding to low level of GSH at ZT8 | [52] |
Carbon tetrachloride is a commonly used hepatotoxicant. In SD rats, administration of CCl4 in the afternoon showed more toxicity than administrated in the morning, the increased toxicity was accompanied by the lowest hepatic GSH levels in the afternoon [36]. Acute CCl4 toxicity was increased in Per2−/− mice. At the 12-h time point after CCl4 treatment, more vacuolations were observed in the liver tissues of Per2-null mice as compared to wild-type (WT) mice, and at 24 h after CCl4 treatment, more severe hepatic necrosis was evident than that occurred in WT mice. A deficit of the Per2 gene enhanced Ucp2 gene expression levels in the liver leading to reduced ATP and increased production of toxic CCl4 derivatives. The absence of Per2 also caused an increased expression of Clock gene [37]. Per2-null mice were not only sensitive to CCl4-induced acute hepatotoxicity, but also to CCl4-induced chronic toxicity and fibrosis. CCl4 caused much more severe liver fibrosis and activated hepatic stellate cell (HSC) in mPer2 null mice as compared to WT mice. Per2-null mice exhibited less efficiency in fibrosis resolution and apoptosis resistance in HSC. Transfection of Per2 cDNA into CCl4-exposed HSC restored apoptosis sensitivity with up-regulation of the TRAIL-R2/DR5 signaling pathway [38].
Acetaminophen hepatotoxicity also displays diurnal variations. When given acetaminophen in the afternoon, toxicity was greater than that given in the early morning [23, 39]. At 8:00, there was no difference of acetaminophen toxicity between Per2-null and WT mice, but at 20:00 when the Per2 expression is highest, Per2-null mice had less liver injury, with less Cyp1a2 expression to bio-activate acetaminophen [40]. In another study, acetaminophen toxicity is greater at Zeitgeber time (ZT)14 than at ZT2, and clock-deficient mice are resistant to the toxicity at ZT14, with prolonged pentobarbital sleep time (PBST), indicating the reduced activation of acetaminophen [41]. Use Bmal1 mutant mice (Bmal1fx/fxCreAlb), the acetaminophen toxicity at ZT12 was decreased, along with decreased APAP protein adducts and altered acetaminophen metabolism kinetics (increased AA-Gluc), possibly due to decreased NADPH-cytochrome P450 oxidoreductase gene expression and activity at ZT12, as compared to WT mice [42].
In Per1, Per2-deficient mice, the ability of AhR ligand dioxin (TCDD) to induce the Cyp1a1 and Cyp1b1 was enhanced, especially with targeted interruption of Per1 [43]. TCDD induction of Cyp1a1 was 23–43 fold greater during the night time (ZT18) than at the day time (ZT6) in WT mice. However, the diurnal variation in the TCDD induction of Cyp1a1 expression was abolished in Per1ldc, Per2ldc, and Per1ldc/Per2ldc mutant mice, suggesting that Per1, Per2 and their timekeeping function in the circadian clockworks mediate the diurnal variation in TCDD induction of Cyp1a1 [44]. Clock mutant Clk/Clk mice failed to show typical oscillation of AhR expression, and BaP (an AhR ligand) induction of Cyp1a1 was disrupted [45].
In Per2−/− mice, bile duct ligation (BDL)-induced liver injury and fibrosis was increased, along with increases in TNFα, TGFβ1, Col1α, and TIMP1 in livers of Per2-null mice as compared to WT mice [46]. In Per1−/− and Per2−/− mice fed on 2% cholestyramine diet, and/or restricted feeding (phase-shift peripheral clock), liver bile acid levels were increased, and the nuclear receptors CAR and PXR were activated, together with the increased serum enzyme AST levels, indicative of liver damage. In these Per1−/− and Per2−/− mice, the circadian expression of key bile acid synthesis and transport genes, including Cyp7a1 and Ntcp, was lost [47].
The hepatotoxic potential of antituberculosis drug isoniazid varied when it was administered at ZT1, ZT9, and ZT17, and the toxicity was highest when isoniazid was given at ZT1 [48]. Chlorzoxazone is a CYP2E1 metabolized drug, and its kinetics and half-life were altered with the diurnal variation of CYP2E1 activity. The value of chlorzoxazone half-life in plasma of the light phase group was significantly longer than the dark phase group, with an increase of 6-hydroxychlorzoxazone production [49]. Acute alcohol-induced higher toxicity at ZT13 than ZT1 when Per1 and Per2 were highly expressed. Per1−/− and Per2−/− mice were less susceptible to alcohol hepatotoxicity, especially in Per1 null mice. Per1 null mice had decreased expression of peroxisome proliferators-activated receptor-gamma and its target genes related to lipid metabolism such as Srebp1, fatty acid synthase (Fas), CD36, diacylglycerol O-acyltransferase 2 (Dgat2), AP2, and adipsin [50]. In primary hepatocytes isolated from Clock mutant Clk/Clk mice and WT mice, diethylnitrosamine (DEN) induced apoptosis and cell death were reduced in Clock-deficient mice, probably due to decreased DEN metabolism [51]. Cadmium hepatotoxicity is independent of metabolic activation; while its mortality was high at ZT8 than ZT20 when the hepatic GSH level was lowest [52].
Thus, alterations of diurnal oscillations would affect drug metabolism, efficacy, and toxicity. On the other hand, drugs could target circadian clock gene expressions to produce biological effects, which will be discussed below.
4. Drugs/toxicants could affect both central and peripheral circadian clock gene expression
The circadian clock is located in both brain and peripheral tissues [8]. The central clock pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, while the peripheral clock is distributed in all peripheral tissues. The liver is the main peripheral tissue under circadian clock regulation [7, 8, 9]. Drugs/toxicants could affect both central and peripheral clock gene expression. For example, Mn is a well-known neurotoxicant producing a Parkinson-like syndrome, but it also produces liver injury. In an attempt to examine the effect of Mn on the central and peripheral clocks, rats were given Mn 1 and 5 mg/kg, ip, every 2 days for 1 month, and the hypothalamus and liver were removed to examine the clock gene expression (Figure 2). The results showed that Mn-induced aberrant expression of circadian clock genes in both hypothalamus and liver, and liver was more sensitive to Mn-induced decreases in clock gene Bmal1, Per1, and increase in Dbp, indicating that both central and peripheral clocks could be disrupted by drugs/toxicants [53]. Another example is chronic alcohol administration. Chronic alcohol consumption produced disruption of circadian clock gene expression in both central (hypothalamus) and peripheral tissues (liver and colon) [54], and the liver appeared to be more susceptible than brain in alterations of metabolic genes and core molecular clock disruption. In addition to the fatty liver and affected the diurnal oscillations of metabolic genes (alcohol dehydrogenase 1, carnitine palmitoyltransferase 1a, Cyp2e1, Phosphoenolpyruvate carboxykinase 1, pyruvate dehydrogenase kinase 4, Ppargc1a, Ppargc1b and Srebp1c), the diurnal oscillations of core clock genes (Bmal1, Clock, Cry1, Cry2, Per1, and Per2) and clock-controlled genes (Dbp, Hlf, Nocturnin, Npas2, Rev-erbα, and Tef) were altered in livers from ethanol-fed mice. In contrast, ethanol had only minor effects on the expression of core clock genes in the suprachiasmatic nucleus (SCN) [55].
5. Drugs affect circadian clock gene expression as a novel target of chronopharmacology
Many drugs/toxicants could affect central and peripheral circadian clock gene expression as targets of chronopharmacology and chronotoxicology [10]. Tables 2 and 3 provide some examples including our work in the field.
Drugs | Animal model (dose, route, time) | Chronopharmacology | References |
---|---|---|---|
Atorvastatin | KM mice; 10–100 mg/kg, po × 30 days | Swollen hepatocyte and feather-like degeneration; increased Cyp7a1, FXR, decreased bile acid transporters; increased expression of Bmal1, Npas2, decrease Per2, Dbp. | [56] |
Metformin | C57 mice; 164 mg/kg in drinking water for 6 weeks | Increase in serum leptin and decreased glucagon levels. Increase in PGC1α, PPARα, AMPK; decrease in ACC in liver; Phase advance circadian clock and metabolic genes in liver and activation of liver casein kinase Iα (CKIα) | [58] |
Oleanolic acid | Apoe−/− mice on HFD, F344 rats; 0.01% OA × 11 weeks | Increased lipid droplets with no change in oxidative stress; increased Bmal1, Clock, and Elovl3, Tubb2a, and Cldn1 decreased Per3, Amy2a5, Usp2, and Thrsp. | [59] |
Resveratrol | C57 mice; fed normal or HFD; 0.1% Res × 11 weeks | Ameliorated HFD-increased plasma leptin, lipids, and BW. Restored rhythmicity of Clock, Bmal1, and Per2; and clock-controlled lipid metabolism genes (Sirt1, PPARa, Srebp-1, Acc1, and Fas). | [60] |
Sea cucumber saponin (SCS) | ICR mice; 0.03% SCS diet night feeding × 2 weeks | Improve serum lipid profile; restore rhythmicity of PPARα, Srebp1, Cpt, and FAS; restore nighttime feeding-disrupted clock gene expression. | [61] |
Zuotai | KM mice; 10 mg/kg, po × 7 days | Decreased the amplitude of Clock, Npas2, Bmal1; increased Dbp, Nfil3 at 10:00, and increased Nr1d1 at 18:00. No effect on Cry and Per genes. | [62] |
Polyporus and Bupleuri radix | ICR mice, Per2Luc mice 500 mg/kg, po × 3 days, at different ZT and light/dark | Polyporus and Bupleuri radix were effective in manipulating the peripheral circadian clock phase acutely, with stimulation time-of-day dependency in vitro as well as in vivo. | [63] |
Jiao-Tai-Wan | SD normal and model (HFD + PSD × 4 weeks) rats 2.2 g/kg, po × 4 weeks | Increased total sleep time and slow wave sleep time; reversed model rat-induced inflammation markers; increased Cry1, Cry 2, and decreased NF-κB in PBMC. | [64] |
Animal model (dose, route, time) | Chronotoxicology | References | |
---|---|---|---|
Carbon tetrachloride | BABL/C mice 0.6 ml/kg, ip, 2/week × 4 weeks |
Chronic CCl4 produced liver fibrosis, altered the amplitudes, meros, acrophases of clock gene expression; circadian rhythms of Cry2, PPARα and POR were lost. | [65] |
Diethylnitrosamine | KM mice DEN 100 mg/kg, IP+ CCl4 + EtOH × 16 weeks |
Produced HCC, Markedly increased α-fetoprotein; at 10:00, expression of Bmal1 decreased, expressions of Dbp and Rev-erbα increased. | [66] |
Manganese | SD rats 1 and 5 mg/kg, IP, × 4 weeks |
Produced neuroinflammation and dopaminergic neuron loss; decreased expression of Bmal1, clock, Per1, Per2, while increased expression of Dbp and Nr1d1 | [53] |
LPS + Rotenone | SD rats LPS 5 mg/kg, IP ×1, 200 days later, rotenone 0.5 mg/kg, sc × 20 |
Produced neuroinflammation and dopaminergic neuron loss; at the mRNA and protein levels, reduced expression of Bmal1, clock, Per1, Per2, Dbp, Nr1d1, while no effect on Cy1. | [70] |
LPS | ICR mice, LPS 1 mg/kg, IP at ZT4, 10, 16, 22 or at 2, 8, and 26 h after ZT 4 injection | Produced increases in serum TNFa, heart and liver apoptosis; Decrease Per1, Per2 2 h after dose at ZT4 in heart and liver; Increased Per2 8 and 26 h after LPS in heart and liver | [71] |
Alcohol | C57 mice, Per2Luc mice Lieber-DeCarli diet for 30–37 days | Produced steatosis, increased serum TG; diurnal oscillations of Bmal1, Clock, Cry1, Cry2, Per1, and Per2 and clock-controlled genes (Dbp, Hlf, Nocturnin, Npas2, Rev-erba, and Tef) were altered in livers of ethanol-fed mice | [55] |
Alcohol | WT and ClockΔ19 mutant mice received Nanji liquid alcohol diet at ZT4 for 10 weeks | Altered the expression of circadian and metabolism genes in hippocampus, liver, and colon from array analysis; ClockΔ19 affect inflammation and metabolism gene. | [54] |
Metformin is commonly used for type 2 diabetes. In C57 mice, metformin in the drinking water for 6 weeks led to increased serum leptin and decreased glucagon levels. The effect of metformin on liver and muscle metabolism was probably mediated through AMPK activation, resulting in the inhibition of acetyl CoA carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis. Metformin-activated liver casein kinase I α (CKIα) and muscle CKIε, known modulators of the positive loop of the circadian clock, thud resulting in phase advances in the liver and phase delays in the muscle for clock and metabolic gene expressions [58].
Resveratrol is an active ingredient in grapes and red wine and shows beneficial effects in metabolic disorders. In HFD-fed mice, resveratrol restored high-fat diet-induced disorders about the rhythmic expression of clock genes and clock-controlled lipid metabolism, ameliorated the rhythmites of plasma leptin, lipid profiles and whole body metabolic status (respiratory exchange ratio, locomotor activity, and heat production). Meanwhile, resveratrol modified the rhythmic expression of clock genes (Clock, Bmal1, and Per2) and clock-controlled lipid metabolism-related genes (Sirt1, Ppara, Srebp-1c, Acc1, and Fas) [60].
Dietary sea cucumber saponin (SCS) has been shown to have beneficial effects on glucose and lipid metabolism, which is related to the circadian clock. Dietary SCS caused an alteration in rhythms and/or amplitudes of clock genes was more significant in the brain than in liver. In addition, the peroxisome proliferator-activated receptor (PPARα), sterol regulatory element binding protein-1c (SREBP-1c), together with their target genes carnitine palmitoyl transferase, and fatty acid synthase showed marked changes in rhythm and/or amplitude in SCS group mice [61].
Polyporus and Bupleuri radix were popular traditional medicines. Polyporus (Zhulin) is used as a diuresis in the treatment edema, while Bupleuri radix (Chaihu) is used for chronic hepatitis. The Per2Luc mice were used to screen their effects on the circadian clock, and Polyporus was more effective than Bupleuri radix in manipulating the peripheral circadian clock phase-shift, and in promoting time-of-day dependency in vitro as well as in vivo [63].
Jiao-Tai-Wan (JTW), composed of Rhizome Coptidis and Cortex Cinnamomi, is a classical traditional Chinese prescription for insomnia. In obesity-resistant (OR) rats with chronic partial sleep deprivation (PSD) model, 4 weeks of administration of JTW increased total sleep time and total slow wave sleep (SWS) time in OR rats with PSD, and reversed the mode rats elevated serum markers of inflammation and insulin resistance, and these changes were also associated with the up-regulation of Cry1 mRNA and Cry 2 mRNA and the down-regulation of NF-κB mRNA expression in peripheral blood monocyte cells [64].
6. Toxicants affect circadian clock gene expression as a novel target of chronotoxicology
Table 3 lists some examples of known toxicants which disrupted circadian clock gene expression as a mechanism of their acute and chronic toxic effects to both brain and liver.
Chronic diethylenediamine (DEN) administration not only produce hepatocellular carcinoma and markedly enhanced expression of Afp, but also decreased the expression of Bmal1, increased the expression of Dbp and Rev-erbα (Nr1d1) [66]. Circadian disruption is well-known to promote carcinogenesis [67]. In the end-stage of human hepatocellular carcinoma, the expressions of the clock genes, including Bmal1, Per1, Per2, Cry1, and Cry2 were decreased, alone with decreases in clock targeted MT-1, MT-2, and MTF1 (which are considered as biomarkers of HCC). On the other hand, the expression of clock target genes Nr1d1 and Dbp was upregulated as compared with Peri-HCC and normal livers. Peri-HCC also had mild alterations in these gene expressions [68].
Chronic neuroinflammation would aggregate neurotoxic effects of toxicants. Rats received a single injection of LPS at the dose of 5 mg/kg, and 200 days later given repeated injection of low dose of rotenone (0.5 mg/kg, sc, 5/week for 4 weeks), and produced neuroinflammation and loss of dopaminergic neurons in Substantia Nigra, replicate the model of Parkinson’s disease [69]. In this PD model, aberrant expression of circadian clock genes in brain cortex was evident, as evidenced by decreases of core clock gene Bmal1, clock, and Naps2, decreases in circadian clock feedback gene Per1 and Per2, but had no effect on the expression of Cry1 and Cry2, as well as the decreased expression of clock target gene Dbp and Nr1d1 [70].
LPS not only produces inflammation in the brain but also in the liver. ICR mice received LPS (1 mg/kg, IP) at ZT4, ZT10, ZT16, and ZT22, and liver and heart were harvested 2 h later for gene expression analysis. Hepatic expression of Per1 and Per2 was decreased after LPS injection at ZT6, but Per1 was increased 8 and 26 h after LPS injection. Heart speared to be more sensitive than the liver to these changes as at ZT4, both Per1 and Per 2 in the heart were decreased [71].
In clock mutant mice, altered clock and metabolism genes were evident in hippocampus, liver, and colon. Of particular interest was the finding that a high proportion of genes involved in inflammation and metabolism on the array was significantly affected by alcohol and the Clock gene mutation in the hippocampus [54].
Thus, drugs/toxicants could affect central and peripheral circadian clock gene expression as targets of their therapeutic effects and/or toxicity [10].
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.
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.
Acknowledgments
This study is supported in part by the Chinese National Science Foundation (81560592).
References
- 1.
Top D, Young MW. Coordination between differentially regulated circadian clocks generates rhythmic behavior. Cold Spring Harbor Perspectives in Biology. 2017;1-27. pii: a033589. DOI: 10.1101/cshperspect.a033589 - 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/cshperspect.a032516 - 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; 72 :517-549. DOI: 10.1146/annurev-physiol-021909-135821 - 4.
Richards J, Gumz ML. Mechanism of the circadian clock in physiology. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2013; 304 :R1053-R1064. DOI: 10.1152/ajpregu.00066.2013 - 5.
Tahara Y, Shibata S. Circadian rhythms of liver physiology and disease: Experimental and clinical evidence. Nature Reviews. Gastroenterology & Hepatology. 2016; 13 (4):217-226. DOI: 10.1038/nrgastro.2016.8 - 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 clock. Trends in Cell Biology. 2014; 24 (2):90-99. DOI: 10.1016/j.tcb.2013.07.002 - 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-060909-153128 - 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; 2016 Apr 05 - 10.
Dallmann R, Brown SA, Gachon F. Chronopharmacology: New insights and therapeutic implications. Annual Review of Pharmacology and Toxicology. 2014; 54 :339-361. DOI: 10.1146/annurev-pharmtox-011613-135923 - 11.
Froy O. Cytochrome P450 and the biological clock in mammals. Current Drug Metabolism. 2009; 10 :104-115 - 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/iub.1160 - 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: 10.1517/17425255.2011.544251 - 14.
Oda M, Koyanagi S, Tsurudome Y, Kanemitsu T, Matsunaga N, Ohdo S. Renal circadian clock regulates the dosing-time dependency of cisplatin-induced nephrotoxicity in mice. Molecular Pharmacology. 2014; 85 :715-722. DOI: 10.1124/mol.113.089805 - 15.
Zmrzljak UP, Rozman D. Circadian regulation of the hepatic endobiotic and xenobitoic detoxification pathways: the time matters. Chemical Research in Toxicology. 2012; 25 :811-824. DOI: 10.1021/tx200538r - 16.
Levi F, Schibler U. Circadian rhythms: Mechanisms and therapeutic implications. Annual Review of Pharmacology and Toxicology. 2007; 47 :593-628 - 17.
Paschos GK, Baggs JE, Hogenesch JB, FitzGerald GA. The role of clock genes in pharmacology. Annual Review of Pharmacology and Toxicology. 2010; 50 :187-214. DOI: 10.1146/annurev.pharmtox.010909.105621 - 18.
Kelleher FC, Rao A, Maguire A. Circadian molecular clocks and cancer. Cancer Letters. 2014; 342 (1):9-18. DOI: 10.1016/j.canlet.2013.09.040 - 19.
Klaassen CD, Aleksunes LM. Xenobiotic, bile acid, and cholesterol transporters. Pharmacological Reviews. 2010; 62 (1):1-96. DOI: 10.1124/pr.109.002014 - 20.
Zhang YK, Yeager RL, Klaassen CD. Circadian expression profiles of drug-processing genes and transcription factors in mouse liver. Drug Metabolism and Disposition. 2009 Jan; 37 (1):106-115. DOI: 10.1124/dmd.108.024174 - 21.
Ma K, Xiao R, Tseng HT, Shan L, Fu L, Moore DD. Circadian dysregulation disrupts bile acid homeostasis. PLoS One. 2009 Aug 31; 4 (8):e6843. DOI: 10.1371/journal.pone.0006843 - 22.
Xu Y, Li S, Wu Q, Lu Y, Liu J. Circadian- and sex-variations of bile acid synthesis and transport gene expression in livers of mice. Zunyi Yixueyuan Xuebao. 2015; 38 :474-478 - 23.
Lu YF, Jin T, Xu Y, Zhang D, Wu Q, Zhang YK, Liu J. Sex differences in the circadian variation of cytochrome p450 genes and corresponding nuclear receptors in mouse liver. Chronobiology International. 2013; 30 (9):1135-1143. DOI: 10.3109/07420528.2013.805762 - 24.
Zhang YK, Guo GL, Klaassen CD. Diurnal variations of mouse plasma and hepatic bile acid concentrations as well as expression of biosynthetic enzymes and transporters. PLoS One. 2011 Feb 8; 6 (2):e16683. DOI: 10.1371/journal.pone.0016683 - 25.
Le Martelot G, Claudel T, Gatfield D, Schaad O, Kornmann B, Lo Sasso G, Moschetta A, Schibler U. REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis. PLoS Biology. 2009 Sep; 7 (9):e1000181. DOI: 10.1371/journal.pbio.1000181 - 26.
Ferrell JM, Chiang JY. Circadian rhythms in liver metabolism and disease. Acta Pharmaceutica Sinica B. 2015 Mar; 5 (2):113-122. DOI: 10.1016/j.apsb.2015.01.003 - 27.
Liu C, Li S, Liu T, Borjigin J, Lin JD. Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature. 2007 May 24; 447 (7143):477-481 - 28.
Bailey SM, Udoh US, Young ME. Circadian regulation of metabolism. The Journal of Endocrinology. 2014; 222 :R75-R96. DOI: 10.1530/JOE-14-0200 - 29.
Marcheva B, Ramsey KM, Peek CB, Affinati A, Maury E, Bass J. Circadian clocks and metabolism. Handbook of Experimental Pharmacology. 2013; 217 :127-155. DOI: 10.1007/978-3-642-25950-0_6 - 30.
Xu YQ, Zhang D, Jin T, Cai DJ, Wu Q, Lu Y, Liu J, Klaassen CD. Diurnal variation of hepatic antioxidant gene expression in mice. PLoS One. 2012; 7 :e44237. DOI: 10.1371/journal.pone.0044237 - 31.
Zhang D, Jin T, Xu YQ, Lu YF, Wu Q, Zhang YK, Liu J. Diurnal-and sex-related difference of metallothionein expression in mice. Journal of Circadian Rhythms. 2012; 10 :5. DOI: 10.1186/1740-3391-10-5 - 32.
Bélanger PM, Lalande M, Labrecque G, Dore FM. Diurnal variations in the transferases and hydrolases involved in glucuronide and sulfate conjugation of rat liver. Drug Metabolism and Disposition. 1985 May-Jun; 13 (3):386-389 - 33.
Inoue N, Imai K, Aimoto T. Circadian variation of hepatic glutathione S-transferase activities in the mouse. Xenobiotica. 1999 Jan; 29 (1):43-51 - 34.
Ando H, Yanagihara H, Sugimoto K, Hayashi Y, Tsuruoka S, Takamura T, Kaneko S, Fujimura A. Daily rhythms of P-glycoprotein expression in mice. Chronobiology International. 2005; 22 (4):655-665 - 35.
Iwasaki M, Koyanagi S, Suzuki N, Katamune C, Matsunaga N, Watanabe N, Takahashi M, Izumi T, Ohdo S. Circadian modulation in the intestinal absorption of P-glycoprotein substrates in monkeys. Molecular Pharmacology. 2015 Jul; 88 (1):29-37. DOI: 10.1124/mol.114.096735 - 36.
Bruckner JV, Ramanathan R, Lee KM, Muralidhara S. Mechanisms of circadian rhythmicity of carbon tetrachloride hepatotoxicity. The Journal of Pharmacology and Experimental Therapeutics. 2002; 300 :273-281 - 37.
Chen P, Li C, Pang W, Zhao Y, Zhao Y, Dong W, Wang S, Zhang J. The protective role of Per2 against carbon tetrachloride-induced hepatotoxicity. The American Journal of Pathology. 2009; 174 :63-70. DOI: 10.2353/ajpath.2009.080430 - 38.
Chen P, Han Z, Yang P, Zhu L, Hua Z, Zhang J. Loss of clock gene mPer2 promotes liver fibrosis induced by carbon tetrachloride. Hepatology Research. 2010a Nov; 40 (11):1117-1127. DOI: 10.1111/j.1872-034X.2010.00695.x - 39.
Jin T, Zhang D, Xu YQ, Xu SF, Liu J. Lu YF. Diurnal variation of CYP1A in livers of KM mice. Zhongguo Yaoliduli Zazhi. 2013; 26 :161-167 - 40.
Kakan X, Chen P, Zhang J. Clock gene mPer2 functions in diurnal variation of acetaminophen induced hepatotoxicity in mice. Experimental and Toxicologic Pathology. 2011; 63 :581-585. DOI: 10.1016/j.etp.2010.04.011 - 41.
DeBruyne JP, Weaver DR, Dallmann R. The hepatic circadian clock modulates xenobiotic metabolism in mice. Journal of Biological Rhythms. 2014; 29 :277-287. DOI: 10.1177/0748730414544740 - 42.
Johnson BP, Walisser JA, Liu Y, Shen AL, McDearmon EL, Moran SM, McIntosh BE, Vollrath AL, Schook AC, Takahashi JS, Bradfield CA. Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111 :18757-18762. DOI: 10.1073/pnas.1421708111 - 43.
Qu X, Metz RP, Porter WW, Cassone VM, Earnest DJ. Disruption of period gene expression alters the inductive effects of dioxin on the AhR signaling pathway in the mouse liver. Toxicology and Applied Pharmacology. 2009; 234 :370-377. DOI: 10.1016/j.taap.2008.10.016 - 44.
Qu X, Metz RP, Porter WW, Neuendorff N, Earnest BJ, Earnest DJ. The clock genes period 1 and period 2 mediate diurnal rhythms in dioxin-induced Cyp1A1 expression in the mouse mammary gland and liver. Toxicology Letters. 2010; 196 :28-32. DOI: 10.1016/j.toxlet.2010.03.020 - 45.
Tanimura N, Kusunose N, Matsunaga N, Koyanagi S, Ohdo S. Aryl hydrocarbon receptor-mediated Cyp1a1 expression is modulated in a CLOCK-dependent circadian manner. Toxicology. 2011; 290 :203-207. DOI: 10.1016/j.tox.2011.09.007 - 46.
Chen P, Kakan X, Wang S, Dong W, Jia A, Cai C, Zhang J. Deletion of clock gene Per2 exacerbates cholestatic liver injury and fibrosis in mice. Experimental and Toxicologic Pathology. 2013; 65 :427-432. DOI: 10.1016/j.etp.2011.12.007 - 47.
Ma K, Xiao R, Tseng HT, Shan L, Fu L, Moore DD. Circadian dysregulation disrupts bile acid homeostasis. PLoS One. 2009; 4 :e6843. DOI: 10.1371/journal.pone.0006843 - 48.
Souayed N, Chennoufi M, Boughattas F, Haouas Z, Maaroufi K, Miled A, Ben-Attia M, Aouam K, Reinberg A, Boughattas NA. Circadian variation in murine hepatotoxicity to the antituberculosis agent «Isoniazide». Chronobiology International. 2015; 32 (9):1201-1210. DOI: 10.3109/07420528.2015.1078808 - 49.
Khemawoot P, Nishino K, Ishizaki J, Yokogawa K, Miyamoto K. Circadian rhythm of cytochrome P4502E1 and its effect on disposition kinetics of chlorzoxazone in rats. European Journal of Pharmacology. 2007; 574 :71-76 - 50.
Wang T, Yang P, Zhan Y, Xia L, Hua Z, Zhang J. Deletion of circadian gene Per1 alleviates acute ethanol-induced hepatotoxicity in mice. Toxicology. 2013; 314 :193-201. DOI: 10.1016/j.tox.2013.09.009 - 51.
Matsunaga N, Kohno Y, Kakimoto K, Hayashi A, Koyanagi S, Ohdo S. Influence of CLOCK on cytotoxicity induced by diethylnitrosamine in mouse primary hepatocytes. Toxicology. 2011; 280 :144-151. DOI: 10.1016/j.tox.2010.12.005 - 52.
Miura N, Yanagiba Y, Ohtani K, Mita M, Togawa M, Hasegawa T. Diurnal variation of cadmium-induced mortality in mice. The Journal of Toxicological Sciences. 2012; 37 :191-196 - 53.
Li H, Fan X, Luo Y, Song S, Liu J, Fan Q. Repeated manganese administration produced abnormal expression of circadian clock genes in the hypothalamus and liver of rats. Neurotoxicology. 2017 Sep; 62 :39-45 - 54.
Summa KC, Jiang P, Fitzpatrick K, Voigt RM, Bowers SJ, Forsyth CB, Vitaterna MH, Keshavarzian A, Turek FW. Chronic alcohol exposure and the circadian clock mutation exert tissue-specific effects on gene expression in mouse hippocampus, liver, and proximal colon. Alcoholism, Clinical and Experimental Research. 2015 Oct; 39 (10):1917-1929. DOI: 10.1111/acer.12834 - 55.
Filiano AN, Millender-Swain T, Jr JR, Young ME, Gamble KL, Bailey SM. Chronic ethanol consumption disrupts the core molecular clock and diurnal rhythms of metabolic genes in the liver without affecting the suprachiasmatic nucleus. PLoS One. 2013; 8 :e71684. DOI: 10.1371/journal.pone.0071684 - 56.
Li WK, Li H, Lu YF, Li YY, Fu ZD, Liu J. Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice. PeerJ. 2017 May 18; 5 :e3348. DOI: 10.7717/peerj.3348 - 57.
Li WK, Xu YJ, Lu YF, Liu J. Atorvastatin induces hepatic expression of Cyp7a1, Bmal1, and Clock in mice. Zhongguo Yaolixue Tongxun. 2016; 32 :642-643 - 58.
Barnea M, Haviv L, Gutman R, Chapnik N, Madar Z, Froy O. Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner. Biochimica et Biophysica Acta. 2012; 1822 :1796-1806. DOI: 10.1016/j.bbadis.2012.08.005 - 59.
Gabás-Rivera C, Martínez-Beamonte R, Ríos JL, Navarro MA, Surra JC, Arnal C, Rodríguez-Yoldi MJ, Osada J. Dietary oleanolic acid mediates circadian clock gene expression in liver independently of diet and animal model but requires apolipoprotein A1. The Journal of Nutritional Biochemistry. 2013; 24 :2100-2109. DOI: 10.1016/j.jnutbio.2013.07.010 - 60.
Sun L, Wang Y, Song Y, Cheng XR, Xia S, Rahman MR, Shi Y, Le G. Resveratrol restores the circadian rhythmic disorder of lipid metabolism induced by high-fat diet in mice. Biochemical and Biophysical Research Communications. 2015 Feb 27; 458 (1):86-91. DOI: 10.1016/j.bbrc.2015.01.072 - 61.
Wen M, Cui J, Xu J, Xue Y, Wang J, Xue C, Wang Y. Effects of dietary sea cucumber saponin on the gene expression rhythm involved in circadian clock and lipid metabolism in mice during nighttime-feeding. Journal of Physiology and Biochemistry. 2014 Sep; 70 (3):801-808. DOI: 10.1007/s13105-014-0349-9 - 62.
Li H, Li WK, Lu YF, Wei LX, Liu J. The Tibetan medicine Zuotai influences clock gene expression in the liver of mice. PeerJ. 2016 Jan 26; 4 :e1632. DOI: 10.7717/peerj.1632 - 63.
Motohashi H, Sukigara H, Tahara Y, Saito K, Yamazaki M, Shiraishi T, Kikuchi Y, Haraguchi A, Shibata S. Polyporus and Bupleuri radix effectively alter peripheral circadian clock phase acutely in male mice. Nutrition Research. 2017 Jul; 43 :16-24. DOI: 10.1016/j.nutres.2017.05.001 - 64.
Zou X, Huang W, Lu F, Fang K, Wang D, Zhao S, Jia J, Xu L, Wang K, Wang N, Dong H. The effects of Jiao-Tai-Wan on sleep, inflammation and insulin resistance in obesity-resistant rats with chronic partial sleep deprivation. BMC Complementary and Alternative Medicine. 2017 Mar 23; 17 (1):165. DOI: 10.1186/s12906-017-1648-9 - 65.
Chen P, Kakan X, Zhang J. Altered circadian rhythm of the clock genes in fibrotic livers induced by carbon tetrachloride. FEBS Letters. 2010; 584 :1597-1601. DOI: 10.1016/j.febslet.2010.03.019 - 66.
Jin T, Wen GR, Jin H, Lu YF, Liu J. DEN-induced hepatocellular carcinoma is associated with aberrant expression of circadian clock genes. Chengdu Yixueyuan Xuebao. 2012; 8 :363-369 - 67.
Filipski E, Subramanian P, Carrière J, Guettier C, Barbason H, Lévi F. Circadian disruption accelerates liver carcinogenesis in mice. Mutation Research. 2009 Nov-Dec; 680 (1-2):95-105 - 68.
Li H, Lu YF, Chen H, Liu J. Dysregulation of metallothionein and circadian genes in human hepatocellular carcinoma. Chronobiology International. 2017; 34 (2):192-202. DOI: 10.1080/07420528.2016.1256300 - 69.
Huang C, Zhu L, Li H, Shi FG, Wang GQ, Wei YZ, Liu J, Zhang F. Adulthood exposure to lipopolysaccharide exacerbates the neurotoxic and inflammatory effects of rotenone in the Substantia Nigra. Frontiers in Molecular Neuroscience. 2017 May 8; 10 :131. DOI: 10.3389/fnmol.2017.00131 - 70.
Li H, Song S, Wang Y, Huang C, Zhang F, Liu J, Hong JS. Chronic lipopolysaccharide combined with rotenone produces neuroinflammation and aberrant expression of circadian clock genes in rats. Neurotoxicology. Baltimore, USA: Toxicologist, and the poster was presented in 51st SOT on March 19, 2017 (still under review) - 71.
Yamamura Y, Yano I, Kudo T, Shibata S. Time-dependent inhibitory effect of lipopolysaccharide injection on Per1 and Per2 gene expression in the mouse heart and liver. Chronobiology International. 2010; 27 :213-232. DOI: 10.3109/07420521003769111 - 72.
Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: Implications for biology and medicine. Proceedings of the National Academy of Sciences of the United States of America. 2014 Nov 11; 111 (45):16219-16224. DOI: 10.1073/pnas.1408886111 - 73.
Li H, Xu SF, Liu J. Circadian clock gens: New targets of traditional Chinese medicine. Zhonghua Zhongyiyao Zazhi. 2017; 34 :5464-5467 - 74.
Anafi RC, Francey LJ, Hogenesch JB, Kim J. CYCLOPS reveals human transcriptional rhythms in health and disease. Proceedings of the National Academy of Sciences of the United States of America. 2017 May 16; 114 (20):5312-5317. DOI: 10.1073/pnas.1619320114