Showing posts with label drug metabolism enzymes. Show all posts
Epigenetic Regulation of Genes Encoding Drug-Metabolizing Enzymes and Transporters; DNA Methylation and Other Mechanisms
The most common epigenetic mechanism of mammalian genome regulation is DNA methylation, which does not change the genetic code but affects gene expression. Owing to its maintenance of the genomic sequence, DNA methylation is expected to offer an explanation for the controversial phenotypes of certain genetic polymorphisms. It has been recognized that DNA methylation plays a role in the transcriptional regulation of some PK/PD genes. In this review, we describe the impact of various epigenetic mechanisms, especially DNA methylation, on the expression (or activity) of drug metabolism enzymes and transporter genes.Allogenic hematopoietic stem cell transplantation (HSCT) is a well established but complex treatment option for malignant and non-malignant disorders in pediatric patients.
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Since different drug metabolite enantiomers are formed in many metabolic pathways, the other indispensable advantage of CE over HPLC is the possibility of chiral separation without the need of special expensive columns. Recent advances in automated systems have made CE even more popular. The focus of this paper is to review recent studies and advances (mainly from 2000) of drug metabolism reviews by using CE. The review is divided into two parts: (i) principles of CE separation of drugs and their metabolites and (ii) application of CE in drug metabolism studies.
The first part introduces sample preparation, separation and detection modes involved in CE drug metabolism studies. To provide a deeper insight into the achievements, distinction between drug metabolism analysis in vivo and in vitro is made in the second part. Reported methods are discussed and summarized.
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Chemical insults, such as environmental or occupational carcinogenic agents, play a major role in the pathogenesis of many cancers. Many carcinogens exert genotoxic and cytotoxic effects via bioactivation into electrophilic species, a process catalyzed primarily by phase I drug metabolizing enzymes, typically cytochrome P450s. These reactive intermediates can induce DNA and RNA damage, and formation of protein adducts.
The reactive species are often detoxified by phase II drug metabolism enzymes , such as glutathione Stransferases (GSTs), UDP-glucuronosyl transferases (UGTs), sulfotransferase (ST) and N-acetyltransferase (NAT). Phase II enzymes classically conjugate these hydrophobic intermediates to a water-soluble group, thus masking their reactive nature, and allowing subsequent excretion. Therefore, strategies that modulate the levels of phase II enzymes by either pharmacological or nutritional means can lead to enhanced elimination of reactive species.
Agents that preferentially activate phase II over phase I enzymes can be beneficial as chemopreventives. Compounds, such as isothiocyanates and dithiolthiones have been shown to act as transcriptional activators of phase II enzymes. A consensus enhancer element, known as antioxidant response element (ARE), in the regulatory domains of many phase II genes and an ARE-binding transcription factor nuclear factor E2-related factor 2 (Nrf2) have been implicated in the action of many chemopreventive agents. In this review, we will discuss the mechanisms of regulation of phase II enzymes, including the signal transduction events elicited by chemopreventive agents. We will also summarize the data available for these agents in preclinical models of tumorigenesis. Some chemopreventive agents have progressed to various stages of clinical trials, e.g. biomarker studies in healthy volunteers or in susceptible populations. These clinical data will be reviewed. Finally, we will provide a commentary on implementation of discovery and development programs for novel chemopreventive agents that are based on rational drug design, with lead optimization towards a safe and efficacious regimen in man.
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The carcinogenic potency, and other carcinogens and the
expanse of binding of their ultimate metabolites to DNA and proteins are
correlated with the induction of few cytochrome isozymes. Phase II
drug-metabolizing diverse enzymes inactivate chemical carcinogens into less toxic
or inactive metabolites. Several drugs change the rate of activation of
carcinogens by changing the activities of phases I and II drug-metabolizing
enzymes.
The balance of activation reactions relies on the chemical structure
of the agents, and is subjected to various variables that are a concern of this
body, or genetic background, sex, endocrine status, age, diet, and the
existence of various chemicals. It is significant to perceive that the enzymes
comprise in carcinogen metabolism are also involved in the drug metabolism enzymes of a variety of substrates,
and thus the foreword of specific xenobiotics may change the operating level
and the existence of other chemicals.
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