P450酶和转运体的DNA甲基化调控：提示药物反应的个体差异

细胞色素P450酶和转运体的基因多态性已被公认是导致临床上药物反应个体差异的重要原因,但个体间某些代谢酶、转运体的基因型和表型不一致的现象不能完全用基因多态性来解释。表观遗传药理学从表观遗传学的角度来研究遗传因素与药物治疗的关系,为药物反应的个体差异提供了新的解释。P450酶和转运体都受表观遗传因素控制。最常见表观遗传调控机制是DNA甲基化,它不会改变基因的遗传代码,而影响基因的表达。由于它对基因组序列的维护,DNA甲基化可用来解释某些基因多态性与表型的不一致现象。本综述总结了DNA甲基化表观遗传调控机制对P450酶和转运体的基因表达影响的最新进展。     

药物转运体表观遗传调控机制的研究进展

药物转运体在体内药物吸收、分布和排泄过程中发挥着重要的作用。转运体在各组织器官的分布和表达受到表观遗传修饰调控,导致某些药物体内处置过程出现明显的个体差异。随着表观遗传学的发展,基于表观遗传修饰（如DNA甲基化、组蛋白修饰、microRNA干预等）调控药物转运体的相关研究越来越多。对表观遗传调控药物转运体研究进行综述。     

Epigenetic control using natural products and synthetic molecules

The term "epigenetics" is defined as "heritable changes in gene expression that occur without changes in DNA sequence". Recently, it has been revealed that DNA methylation and histone modifications such as acetylation, methylation and phosphorylation are epigenetic mechanisms according to this definition. In other words, these posttranslational modifications are important factors in determining when and where a gene will be expressed. To date, several enzymes that catalyze DNA or histone modifications have been identified, such as DNA methyltransferases and histone deacetylases. Inhibitors and activators of enzymes controlling epigenetic modifications are considered useful not only as tools for the elucidation of cellular and biological phenomena, but also as therapeutic agents, since disruption of the balance of epigenetic networks is known to cause some disease states such as cancer. In this review, we present natural products and synthetic molecules that inhibit or activate enzymes catalyzing DNA methylation or histone modifications, and discuss the potential of epigenetic therapy.     

Targeting epigenetic mechanisms: potential of natural products in cancer chemoprevention

The term epigenetics is defined as heritable changes in gene expression patterns that occur without changes in DNA sequence. Epigenetic changes according to this definition are achieved by methylation of cytosine bases in the DNA and by histone modifications, such as acetylation, methylation or phosphorylation. These modifications play an important role in regulating gene expression and the existence of an epigenetic code which maintains these modifications even upon cell division has been underlined by many investigations. Targeting the enzymes which catalyze DNA methylation or histone modifications may be a possibility not only for cancer therapy but also for chemoprevention since disruption of epigenetic balance is known to cause diseases such as cancer. In this review, we want to present the key epigenetic targets. We highlight natural products that modulate these epigenetic mechanisms and show their potential for cancer chemoprevention.     

Pharmacoepigenetics: an element of personalized therapy?

Introduction: Epigenetics is a rapidly growing field describing heritable alterations in gene expression that do not involve DNA sequence variations. Advances in epigenetics and epigenomics have influenced pharmacology, leading to the development of a new specialty, pharmacoepigenetics, the study of the epigenetic basis for the individual variation in drug response.

Areas covered: We present an overview of the major epigenetic mechanisms and their effects on the expression of drug metabolizing enzymes and drug transporters, as well as the epigenetic status of drug protein targets affecting therapy response. Recent advances in the development of pharmacoepigenetic biomarkers and epidrugs are also discussed.

Expert opinion: There is growing evidence that pharmacoepigenetics has the potential to become an important element of personalized medicine. Epigenetic modifications influence drug response, but they can also be modulated by drugs. Moreover, they can be monitored not only in the affected tissue, but also in body fluids. Nevertheless, there are very few examples of epigenetic biomarkers implemented in the clinical setting. Explanation of the interplay between genomic and epigenomic changes will contribute to the personalized medicine approach. Ultimately, both genetic biomarkers and epigenetic mechanisms should be taken into consideration in predicting drug response in the course of successful personalized therapy.     

Epigenetics of drug abuse: predisposition or response

Drug addiction continues to be a serious medical and social problem. Vulnerability to develop an addiction to drugs is dependent on genetic, environmental, social and biological factors. In particular, the interactions of environmental and genetic factors indicate the significance of epigenetic mechanisms, which have been found to occur in response to illicit drug use or as underlying factors in chronic substance abuse and relapse. Epigenetics is defined as the heritable and possibly reversible modifications in gene expression that do not involve alterations in the DNA sequence. This review discusses the various types of epigenetic modifications and their relevance to drug addiction to elucidate whether epigenetics is a predisposing factor, or a response to, developing an addiction to drugs of abuse.     

Targeting the histone orthography of cancer: drugs for writers,erasers and readers

Gene expression is dynamically controlled by epigenetics through post-translational modifications of histones, chromatin-associated proteins and DNA itself. All these elements are required for the maintenance of chromatin structure and cell identity in the context of a normal cellular phenotype. Disruption of epigenetic regulation is a common event in human cancer. Here, we review the key protein families that control epigenetic signalling through writing, erasing or reading specific post-translational modifications. By exploiting the leading role of epigenetics in tumour development and the reversibility of epigenetic modifications, promising novel epigenetic-based therapies are being developed. In this article, we highlight the emerging low MW inhibitors targeting each class of chromatin-associated protein, their current use in preclinical and clinical trials and the likelihood of their being approved in the near future.     

Cadmium and its epigenetic effects

Cadmium (Cd) is a toxic, nonessential transition metal and contributes a health risk to humans, including various cancers and cardiovascular diseases; however, underlying molecular mechanisms remain largely unknown. Cells transmit information to the next generation via two distinct ways: genetic and epigenetic. Chemical modifications to DNA or histone that alters the structure of chromatin without change of DNA nucleotide sequence are known as epigenetics. These heritable epigenetic changes include DNA methylation, post-translational modifications of histone tails (acetylation, methylation, phosphorylation, etc), and higher order packaging of DNA around nucleosomes. Apart from DNA methyltransferases, histone modification enzymes such as histone acetyltransferase, histone deacetylase, and methyltransferase, and microRNAs (miRNAs) all involve in these epigenetic changes. Recent studies indicate that Cd is able to induce various epigenetic changes in plant and mammalian cells in vitro and in vivo. Since aberrant epigenetics plays a critical role in the development of various cancers and chronic diseases, Cd may cause the above-mentioned pathogenic risks via epigenetic mechanisms. Here we review the in vitro and in vivo evidence of epigenetic effects of Cd. The available findings indicate that epigenetics occurred in association with Cd induction of malignant transformation of cells and pathological proliferation of tissues, suggesting that epigenetic effects may play a role in Cd toxic, particularly carcinogenic effects. The future of environmental epigenomic research on Cd should include the role of epigenetics in determining long-term and late-onset health effects following Cd exposure.     

MicroRNAs and cancer epigenetics

The term epigenetics refers to all heritable changes in gene expression that are not associated with concomitant alterations in the DNA sequence. Reversible DNA methylation and histone modifications are the hallmarks of epigenetic gene regulation. MicroRNAs (miRNAs) are a recently discovered category of noncoding RNAs with important regulatory functions. Aberrancies in both the epigenetic and in the miRNA regulation of genes have been documented in cancer. An increasing number of studies are showing that the abnormalities of the epigenome and of the miRNome are not independent and could be explained both by an epigenetic regulation of miRNA expression and by miRNA control on components of the epigenetic machinery. A deeper understanding of this correlation could lead to new therapeutic avenues.     

细胞色素P450酶的表观遗传学调控及研究进展

细胞色素P450（CYPs）家族是体内重要的药物代谢酶,其功能主要是代谢临床药物及外源性物质。长期以来,CYP450酶的个体间功能活性差异往往被认为是由基因多态性所导致。然而随着研究的日益深入,人们发现基因序列的改变并不能完全解释CYP450酶的个体间活性差异。表观遗传学作为研究DNA序列未发生变化而基因表达发生可遗传变异的学科,可作为重要研究手段进一步解释CYP450酶的个体差异。该学科主要研究内容包括DNA甲基化、组蛋白翻译后修饰和RNA编辑等。本文就各主要CYP450酶的表观遗传学调控研究进行综述并讨论其在药物代谢和临床应用中的意义。     

DNA甲基化与药物效应的表观遗传药理学研究进展

除遗传多态性外,DNA序列的表观遗传修饰,也可造成基因表达水平的改变,从而影响个体对药物的反应,造成药物效应的个体差异。表观遗传药理学研究整个环境因素对药物的影响,为临床药物效应的个体差异提供了新的作用机制学说。DNA甲基化是表观遗传修饰的主要机制之一,本文综述了DNA甲基化对药物效应的影响及环境因素对DNA甲基化的影响。     

A new paradigm in toxicology and teratology: altering gene activity in the absence of DNA sequence variation

'Epigenetics' is a heritable phenomenon without change in primary DNA sequence. In recent years, this field has attracted much attention as more epigenetic controls of gene activities are being discovered. Such epigenetic controls ensue from an interplay of DNA methylation, histone modifications, and RNA-mediated pathways from non-coding RNAs, notably silencing RNA (siRNA) and microRNA (miRNA). Although epigenetic regulation is inherent to normal development and differentiation, this can be misdirected leading to a number of diseases including cancer. All the same, many of the processes can be reversed offering a hope for epigenetic therapies such as inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases, histone deacetylases, and RNAi therapeutics. 'In utero' or early life exposures to dietary and environmental exposures can have a profound effect on our epigenetic code, the so-called 'epigenome', resulting in birth defects and diseases developed later in life. Indeed, examples are accumulating in which environmental exposures can be attributed to epigenetic causes, an encouraging edge towards greater understanding of the contribution of epigenetic influences of environmental exposures. Routine analysis of epigenetic modifications as part of the mechanisms of action of environmental contaminants is in order. There is, however, an explosion of research in the field of epigenetics and to keep abreast of these developments could be a challenge. In this paper, we provide an overview of epigenetic mechanisms focusing on recent reviews and studies to serve as an entry point into the realm of 'environmental epigenetics'.     

Epigenetic targets of some toxicologically relevant metals: a review of the literature

The term epigenetics was coined in the context of developmental studies, but the meaning of the term has evolved over time. Epigenetic modulators of gene expression are now known to include DNA methylation, chromatin modifications and noncoding RNAs. The observation that epigenetic changes can be transmitted transgenerationally makes the science of epigenetics very relevant to the field of environmental and molecular toxicology. Heavy metals constitute an important class of environmental contaminants that have been known to influence gene expression directly by binding various metal response elements in the target gene promoters. Recent research suggests that metals can also influence gene expression through epigenetic mechanisms; this adds a new twist to the complexity of metal‐mediated gene expression. Here, we review recent studies that investigate the epigenetic, gene expression, and biological effects of various inorganic and organic forms of heavy metals, such as cadmium, arsenic, nickel, chromium, methylmercury, lead, copper and organotin compounds. Copyright © 2012 John Wiley & Sons, Ltd.     

Epigenetic mechanisms in metal toxicity

The true understanding of epigenetics evolved over time as our knowledge on DNA methylation and chromatin modifications and their effects on gene expression increased. The current flurry of research on epigenetics and the increasing documentation of the effects of various environmental factors on DNA methylation, chromatin modification, as well as on the expression of small non-coding RNAs (ncRNAs) have expanded the scope of research on the etiology of various diseases including cancer. The current review briefly discusses various molecular mechanisms of epigenetic regulation of gene expression, and expands the discussion with examples of heavy metal-induced alterations of gene expression and the associated epigenetic changes.     

Epigenetic mechanisms in metal toxicity

The true understanding of epigenetics evolved over time as our knowledge on DNA methylation and chromatin modifications and their effects on gene expression increased. The current flurry of research on epigenetics and the increasing documentation of the effects of various environmental factors on DNA methylation, chromatin modification, as well as on the expression of small non-coding RNAs (ncRNAs) have expanded the scope of research on the etiology of various diseases including cancer. The current review briefly discusses various molecular mechanisms of epigenetic regulation of gene expression, and expands the discussion with examples of heavy metal-induced alterations of gene expression and the associated epigenetic changes.