Chronopharmacological strategies: Intra- and inter-individual variability of molecular clock

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Abstract

In all living organisms, one of the most indispensable biological functions is the circadian clock (suprachiasmatic nuclei; SCN), which acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24 h cycles. Circadian rhythms regulate diverse physiologic processes, including homeostatic functions of steroid hormones and their receptors. Perturbations of these rhythms are associated with pathogenic conditions such as depression, diabetes and cancer. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior. Clock gene regulates several diseases such as cancer, metabolic syndrome and sleep etc. CLOCK mutation affects the expression of rhythmic genes in wild-type (WT) tissue, but also affects that of non-rhythmic genes. On the other hand, the change of the drug pharmacodynamic and pharmacokinetic (PK/PD) parameters are influenced by not only inter-individual variability but also intra-individual variabilities of medications. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The mechanisms underlying chronopharmacological findings should be clarified from viewpoint of clock genes. On the other hand, several drugs have an effect on molecular clock. Thus, the knowledge of intra- and inter-individual variability of molecular clock should be applied for the clinical practice. Therefore, we introduce the regulatory system of biological rhythm from viewpoints of clock genes and the possibility of pharmacotherapy based on the intra- and inter-individual variability of clock genes.

Introduction

The study on the individualization of pharmacotherapy has been carried out aiming at further improvement of pharmacotherapy. The study of correlations between genome variation and phenotype diversity is a key theme in modern biosciences. Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity [1]. By doing so, pharmacogenomics aims at developing rational means to optimize drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of “personalized medicine”; in which drugs and drug combinations are optimized for each individual's unique genetic makeup [2].

The conventional method of classifying the pharmaceutical variations stated that there are two major classes of variabilities such as inter-individual and intra-individual variabilities. Basic pharmacotherapeutic researches have focused only on the inter-individual variability of drug pharmacodynamic and pharmacokinetic (PK/PD). The pharmacogenomic/pharmacogenetic studies have disclosed the molecular mechanism of the inter-individual variability taking different levels ranging from the different heritable chromosomes to the protein polymorphism due to point mutations among species of the same gene at the translation and post-translation stages [3], [4], [5]. This traditional way of thinking stated that diseases are emerged due to either increased or decreased genetic expression of certain molecular targets. This hypothesis did not take the intra-individual variability in its consideration. It was before the discovery of the clock and clock-controlled genes in mammal in 1997 that enables practitioners to use medications more effectively and safely [6].

The intra-individual variability as well as inter-individual variability should be considered to aim at further improvement of rational pharmacotherapy. Because many drugs vary in potency and/or toxicity associated with the rhythmicity of biochemical, physiological and behavioral processes [7], [8], [9], [10], [11], [12], [13]. Theoretically, it has been argued that drug administration at certain times of the day should improve the outcome of pharmacotherapy. This has been accepted by the medical community and/or described in an interview form for the treatment of nocturnal asthma, allergic rhinitis, arthritis, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. However, several drugs are still given without regard to the time-of-day. The chronopharmacological findings should be systematically summarized in an applicable format for clinical practice.

In all living organisms, one of the most indispensable biological functions is the circadian clock (suprachiasmatic nuclei; SCN), which acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24 h cycles [14], [15]. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior [16]. Circadian rhythms regulate diverse physiologic processes, including homeostatic functions of steroid hormones and their receptors. Perturbations of these rhythms are associated with pathogenic conditions such as depression, diabetes, and cancer. Clock gene regulates several diseases such as cancer, metabolic syndrome and sleep etc. CLOCK mutation affects the expression of rhythmic genes in wild-type (WT) tissue, but also affects that of non-rhythmic genes. The knowledge of intra- and inter-individual variability of molecular clock should be applied for the clinical practice. The monitoring of rhythm, overcome of rhythm disruption and manipulation of rhythm from viewpoints of molecular clock are essential to improved progress and diffusion of chronopharmacotherapy. Such approach should be achieved by the new challenges in drug delivery system that match the circadian rhythm (Chrono-DDS) [11], [12]. Recent strategy on pharmacotherapy has been focused on gene delivery and antibody delivery targeting specific molecular for some diseases. Clock genes should be also one of important candidates. Therefore, the aim of this review is to provide an overview of the regulatory system of biological rhythm from viewpoints of clock genes and the possibility of pharmacotherapy based on the intra- and inter-individual variability of clock genes.

Section snippets

Biological clock

The SCN of the anterior hypothalamus are the site of the circadian pacemaker in mammals [14]. Like any timing system, the circadian clock is made up of three components [15], [16], [17]: an input pathway adjusting the time, a central oscillator generating the circadian signal, and an output pathway manifesting itself in circadian physiology and behavior. The daily changes in light intensities are thought to be the major environmental cue involved in circadian entrainment. Light-signals are

Intra- and inter-individual variability of clock genes and chronopharmacological strategy

Clock genes “the intra-individual variables” are subjected to genetic variations “the inter-individual variability”. Clock gene in Clock mutant mice has a point mutation causing the deletion of exon 19 (51 amino acids) of the clock gene, thus synthesizing mutant CLOCK protein (CLOCK∆19) deficient in transcriptional activity [26]. CLOCK mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase–response curve amplitude [27]. Comparing between these two

Chronobiology of physiological function and diseases

Chronotherapeutic approach is based on the presence of 24 h rhythms in physiological functions and diseases. The knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy (chronotherapy) [33], [34]. Chronotherapy is especially relevant in the following cases. The risk and/or intensity of the symptoms of disease vary predicably over time as exemplified by allergic rhinitis,

Chronopharmacodynamics

Biological rhythms not only impact the pathophysiology of diseases, but the pharmacokinetics and pharmacodynamics of medications. Chronopharmacology is the investigative science that elucidates the biological rhythm dependencies of medications. Biological rhythms at the cellular and subcellular level can give rise to significant dosing time differences in the pharmacodynamics of medications that are unrelated to their pharmacokinetics. This phenomenon is termed chronesthesy. Rhythms in receptor

Chronopharmacokinetics

Chronopharmacokinetic studies have been reported for many drugs in an attempt to explain chronopharmacological phenomena and demonstrate that the time of administration is a possible factor of variation in the pharmacokinetics of a drug. Time-dependent changes in pharmacokinetics may proceed from 24 h rhythms at each process, e.g. absorption, distribution, metabolism and elimination. Thus, 24 h rhythms in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow,

The disruption and maintenance of biological rhythms

The circadian clock system is necessary to adapt endogenous physiological functions to daily variations in environmental conditions. Abnormality in circadian rhythms, such as the sleep-wake cycle and the timing of hormonal secretions, is implicated in various physiological and psychiatrical disorders. Recent molecular studies have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of 24 h cycles of physiology and behavior. It has been

The adjustment and manipulation of biological rhythms

The 24 h rhythms of physiology and behavior are influenced by various environmental factors such as feeding schedules, genetic factors and social interactions as well as lighting condition and several drugs [13], [15], [37], [65]. Since the period of the central circadian pacemaker in humans is slightly longer than 24 h described above, synchronization of the circadian system with the light–dark cycle occurs by daily phase-advances of the circadian clock. In humans, the time-of-day-dependent

Necessary of clock gene delivery on cancer therapy

The effectiveness and toxicity of many drugs vary depending on the relationship between the dosing schedule and the 24 h rhythms of biochemical, physiological and behavioral processes. In addition, several drugs can cause alterations to the 24 h rhythms leading to illness and altered homeostatic regulation. The alteration of biological rhythm is a new concept of adverse effects. The latter can be minimized by optimizing the dosing schedule [60]. A large body of literature exists demonstrating the

Conclusions

Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior. Clock gene regulates several disease such as cancer, metabolic syndrome and sleep etc. Comparison between the tissues from WT and Clock mutant mice reveals that the CLOCK mutation affects the expression of many genes that are rhythmic in WT tissue, but also profoundly affects many non-rhythmic genes. So, clock-controlled genes can show either rhythmic or constant levels

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