Glucocorticoids Drug Metabolism - Free Essay Example

Sample details Pages: 11 Words: 3366 Downloads: 9 Date added: 2017/06/26 Category Science Essay Type Argumentative essay Tags: Drugs Essay Did you like this example? The Role of Glucocorticoid Receptor in the Regulation of Drug Metabolism Introduction Glucocorticoids are extremely important in our life due to their pivotal roles in maintaining homeostasis and coping with stress. Tremendous attention has focused on glucocorticoids because of their wide usage in the treatment of autoimmune and inflammatory diseases and their implications to the pathogenesis of many wide-spread disorders, such as hypertension, diabetes, obesity, etc. Many pathophysilogical effects of glucocorticoids are contributed by their transcriptional regulation of approximately 10% of our genes (Buckingham, 2006) and these effects are predominantly dependent on the interaction between glucocorticoids and the glucocorticoid receptor (GR), a ligand-activated transcription factor. Don’t waste time! Our writers will create an original "Glucocorticoids Drug Metabolism" essay for you Create order Although a variety of physiological functions, such as immune response, metabolism, growth, etc, could be closely related to the GR-mediated gene regulation, this review will mainly focus on the GR-mediated enzyme regulation and its crucial role on drug metabolism in human. It has been appreciated that nuclear receptors play important role in xenobiotic response by regulating expression and/or activity of drug-metabolizing enzymes, thereby modifying the targeted concentrations of the drug and altering the therapeutic drug response. With the development of molecular biology, structure biology, genetics and metabolism studies, tremendous effort has been made to understand the fundamental functions of nuclear receptor superfamily, which makes up a complex regulatory network with extensive cross communication in regulating the xenobiotic response between them. GR becomes my focus not only because of the essential physiological process aforementioned but the key role it plays in drug metabolism. Exploring and understanding the fundamental mechanisms underpinning the actions of GR is critical and is of great help to explain the drug response and some pathophysilogical effects of glucocorticoids as well. GR: structure Glucocorticoid receptor belongs to subfamily 3C of nuclear receptor superfamily and is the first cloned human steroid receptor (Hollenberg et al., 1985). Two protein isoforms of GR, termed hGR alpha (777 amino acids) and hGR beta (742 amino acids) are distinguished by the last 15 amino acids at the C-terminal end and differed binding properties with glucocorticoids. hGR alpha is transcriptionally active while hGR beta is unable to bind glucocorticoids or induce gene transcription. Some studies suggest that it may act as a negative regulator of glucocorticoid action and contribute the tissue sensitivity to glucocorticoids (Bamberger et al., 1995). Three major functional domains: N-terminal domain (NTD), DNA binding domain (DBD) and ligand-binding domain (LBD) are well studied for the GR. Within N-terminal domain, a major activational function domain1 (AF1) is required to enhance maximal transcriptional activity. The DBD contains the most conserved amino acid sequence and comprises two cysteine-rich zinc fingers, which are essential for GR dimerisation and site-specificity of DNA binding. The C-terminal located LBD is responsible for recognition and ligand binding. It also contains the other activational function domain2 (AF2) and this AF2 is also important in regulating the transcriptional activity of GR. In addition to the three major domains, a D-domain or hinge region links DBD and LBD is considered playing a role in GR nuclear translocation (Kumar and Thompson, 2005; Buckingham, 2006). Recent progresses in crystallographic studies solve the crystal structure of the DBD and LBD of the GR, which reveal more insights into the structure: function relationship of GR and help to better understand the importance of molecular organization in the transcriptional activity as well (Lu et al., 2006). GR: activation and gene regulation A chain of impressive reactions occur during the activation of GR and resulting gene regulation. As a ligand-activated transcription factor, the cytoplasm located inactive GR is bound to heat shock protein 90 (hsp90) and other proteins which prevent the nuclear localization of this unoccupied GR. After binding to specific ligand, such as glucocortcoids, the GR is activated and dissociate the oligomeric protein complex, undergoing nuclear translocation, dimerizing via the essential DBD, binding with glucocorticoid response elements (GREs) in the promoter region, recruiting and interacting with other regulatory proteins to induce or repress the expression of targeted genes (Hayashi et al., 2004; Buckingham, 2006). In addition to the direct regulate gene transcription by activated GR binding with GREs, some recent research suggest the indirect regulatory role of GR via protein-protein interactions (Buckingham, 2006). In this manner, GR could interact with other transcription factors, such as NF-B and AP-1, to reduce the expression of pro-inflammatory genes. Most notably in drug metabolism, an extensive cross-talk between GR and other nuclear receptors exists, such as pregnane X receptor (PXR), constitutive androstane receptor (CAR) and retinoic X receptor (RXR) and it further complicates the GR-mediated gene regulation and drug response (Pascussi et al., 1999; Pascussi et al., 2000b; Pascussi et al., 2004; Dvorak et al., 2005). Role of GR: Cytochrome P450 3A4 CYP3A4 is the most important and abundant cytochrome p450 in human liver. It has the largest range of substrates and plays a pivotal role in steroid catabolism and xenobiotic metabolism. The fundamental mechanism underlying the transcriptional activation of CYP3A4 is complex and involves many nuclear receptors, such as PXR, GR, vitamin D receptor and CAR. In fact, several observations indicate the important role of GR in the inducible gene expression of CYP3A4. First of all, glucocortcoids are the classic inducers of CYP3A4 in mammals; secondly, RU486, an antagonist of GR, block the dexamethasone-mediated transcriptional activation of CYP3A4 in HepG2 cells cotransfected with GR and CYP3A4 promoter (Ogg et al., 1999). Although CYP3A4 is highly inducible by glucocortcoids, theres few evidence for the direct interaction of GR with the CYP3A4 promoter since no consensus glucocorticoid receptor response element (GRE) existed in CYP3A genes. Several possible hypotheses account for the role of GR in the transcription regulation of CYP3A4 have been projected (El-Sankary et al., 2002). Either a nonconsensus GRE present in the CYP3A4 promoter region could be used to explain the direct interaction of GR with the CYP3A4 promoter or as previously mentioned via an indirect manner, GR could interact with other transcription factors thereby interacting with the CYP3A4 promoter to induce CYP3A4. Opposed to these hypotheses, study from a GR-knockout mice model shows that GR is not essential for the glucocortcoids-mediated induction of CYP3A (Schuetz et al., 2000). Although someone may argue that such knock-out animal study may cause some other compensating pathway; further extrapolating result from rodents is not scientifically reasonable. Hence the regulation role of GR in CYP3A4 expression is still debatable. On the other hand, since PXR has been demonstrated as a major steroid hormone nuclear receptor in regulation the CYP3A4 gene expression (Lehmann et al., 1998), an indirect evidence for the latter hypothesis could be supported by the interactive regulatory cross communication between GR and other nuclear receptors, especially PXR, CAR and RXR (Pascussi et al., 2000a; Pascussi et al., 2000b; Gerbal-Chaloin et al., 2002). It is highly possible that GR indirectly contributes to the inducible gene regulation of CYP3A4 by interacting and controlling the expression of PXR, CAR and RXR. Indeed, in studies using human hepatocytes, dexamethasone has shown to enhance the PXR, CAR and RXR expression, leading to enhanced PXR-mediated CYP3A4 expression (Pascussi et al., 2000a; Pascussi et al., 2000b). Unfortunately, no convincing evidence has been provided in relation to the direct implication of GR in CYP3A4 gene induction. Furthermore, more complicated phenomenon has been observed recently using placental trophoblast cell line (Pavek et al., 2007). In this study, GR-mediated CYP3A4 induction indicates hepatocyte-specific regulation pattern and some other hepatocyte-specific transcription factors are required for the GR-CYP3A4 gene regulation process. It is of my point that since most of the studies have been done in vitro using human hepatocytes, in vivo situation could be far more complex especially in human body. Clearer picture depicting the role of GR in CYP3A4 gene expression is intriguing and it will be extreme important in understanding the regulation mechanism of this crucial enzyme, which ultimately leads to better predictions of clinical important drug-drug interactions. Role of GR: Cytochrome P450 2C9 2C19 In contrast to CYP3A4, CYP2C9 is secondly most abundant drug-metabolizing enzymes in human liver and accounts for the metabolism of a wide range of clinically important therapeutic agents, such as phenytoin, S-warfarin and some nonsteroidal anti-inflammatory drugs. Although a great amount of knowledge has been known about this enzyme including genetic polymorphism, pharmacology, etc, very little is known about the molecular mechanisms underlying the transcriptional regulation of CYP2C9. Specifically, it has been demonstrated that CYP2C9 is inducible by dexamethasone (DEX) in primary human hepatocytes and the role of GR related to this inducible CYP2C9 gene expression has been carefully investigated by Sabine and his coworkers (Gerbal-Chaloin et al., 2002). In addition to the transcriptional regulation by hCAR and PXR, deletional analysis of CYP2C9 regulatory region in the presence or absence of cotransfected GR and directed mutagenesis studies have been carried out to characterize the location of the functional GRE in CYP2C9 regulatory region; Further gel shift assays prove the direct interaction between hGR with CYP2C9-GRE. These observations provide a convincing evidence for direct implication of GR in the inducible CYP2C9 expression and shed light for further understanding this crucial enzyme gene regulation. In stead of using human primary hepatocytes, some research group investigated the role of GR in the transcriptional regulation of CYP2C9 in placental cell line. Interestingly, unlike the hepatocytes, due to lack of hepatocyte-specific transcriptional factors, such as hepatocyte nuclear factor 4a (HNF4a), CYP2C9 is not inducible in this special placental cell line (Pavek et al., 2007). Similar observation seen in the aforementio ned CYP3A4, which might indicates the tissue-specificity regulatory role of GR-CYP gene regulation. CYP2C19 is also abundantly expressed in the liver and several clinically important agents undergo CYP2C19-mediated oxidative metabolism including omeprazole, diazepam, etc. A high interindividual variability related to CYP2C19 expression has been observed, which may partially contributed by the nuclear receptor-regulated CYP2C19 gene expression. By examining the transcriptional regulation of CYP2C19, the functional GR and CAR response element have been identified in the CYP2C19 promoter and mutation of GRE abolishes DEX-induced CYP2C19 expression in human hepatocytes (Chen et al., 2003). This provides clear evidence showing the importance of GR in regulating CYP2C19 expression. Role of GR: Cytochrome P450 2B6 The role of GR in the xenobiotic-induced expression of CYP2B in rodents has been shown as evidenced by several groups. For example, GREs have been located in mouse CYP2B10 and rat CYP2B2 (Jaiswal et al., 1990; Stoltz et al., 1998) and GR has been shown as a requirement for maximal induction of these 2 genes in rodents (Shaw et al., 1993; Honkakoski and Negishi, 1998). This arise the question of the role of GR in the regulation of human CYP2B6 expression.CYP2B6 is a member of Cytochrome P450 group and has been considered as playing minor role in drug metabolism. But recent studies suggest the importance of CYP2B6 by taking into account of the fact that CYP2B6 actually involve in metabolizing about 25% of all the pharmaceutical agents. Notably, CYP2B6 is also inducible and hepatic expression is highly variable between individuals (Xie and Evans, 2001). Due to increased attention and urgence in understanding the molecular determinants of CYP2B6 regulation, the role of GR in the CYP2B6 regulation has been evaluated by several research groups. For example, by a study using primary human hepatocytes cotransfected of hGR and hPXR or hCAR with CYP2B6 reporter constructs (Wang et al., 2003), GR seems to function synergistically with hPXR and hCAR to regulate the xenobiotic-induced CYP2B6 expression while GR alone dose not exert this effect in human hepatocytes. As previously mentioned about the role of GR in gene regulation, it again suggest that activated GR could act as a coactivator to enhance the hPXR and hCAR-mediated CYP2B6 expression. Role of GR: phase II drug-metabolizing enzymes Glucuronidation, sulfation, and glutathione conjugation are the three most important conjugation reactions in phase II drug metabolism. In addition to the essentiality of GR in phase I drug metabolizing enzymes that I summarized above, GR seems also play role in regulating these three phase II drug metabolizing enzymes. In a UDP-glucuronosyltransferase (UGT) 1A1 reporter gene study by Toru and his coworkers (Usui et al., 2006), a dose-dependent induction of UGT1A1 by DEX has been observed and co-expression of hGR in the transfected HepG2 cell line enhance the induction by 7-fold; Further treatment with GR antagonist RU486 inhibit the DEX-mediated UGT1A1 induction. The data suggest the important role of GR on the effective induction of UGT1A1 in cultured human hepatocytes. In terms of human sulfotransferase (SULTs), unlike the rat SULT1A1gene that GR mediates the transactivation of this gene expression (Fang et al., 2003); the expression of human SULT1A1 is not affected by glucocorticoids treatment in primary human hepatocytes (Duanmu et al., 2002). On the other hand, human SULT1A3 gene is induced by glucocorticoids through a GR-mediated transactivation in human HepG2 cells and the GRE is identified for the SULT1A3 (Bian et al., 2007). However, human hydroxysteroid sulfotransferase (SULT2A1) gene expression is induced by glucocorticoids through a more complex nuclear receptor-mediated mechanism, with some involvement of GR while PXR is considered as playing a major role in SULT1A3 gene regulation (Duanmu et al., 2002). Glutathione S-transferase (GST) mediated detoxification of electrophilic chemicals is pivotal in preventing toxicity in human body. Unlike the rodent models, little is known about the role of GR in the GST gene regulation. Interestingly, some research conducted to evaluate the role of GR on GSTA2 expression (Falkner et al., 2001). In transfected HepG2 cells, activated GR repress the expression of GSTA2 with low concentration of DEX; while with high concentration of DEX, GSTA2 is inducible via a PXR-dependent mechanism. However, extrapolation of these results to human is not reliable and requires future studies. Conclusion In this review, some clinical important phase I and phase II drug-metabolizing enzymes are examined related to the role of GR in the gene transcriptional regulation in human. Notably, these enzymes play pivotal role in xenobiotic metabolism and nuclear receptor-mediated xenobiotic regulation to a large extent rely on the transcriptional regulation of these enzymes expression. Molecular mechanism underlying the gene regulation has been elusive as the role of nuclear receptors being characterized. GR, as the first cloned human steroid receptor, seems play a controversy role in terms of its relative contribution and regulation mechanisms in different phase I and phase II drug-metabolizing enzymes. Although this article mainly focus on research data in human, examinations of the species difference and in vitro- in vivo correlation are crucial given that significant amount of available information deal with rodent models. Carefully investigating these results could help us better understand the complicated role of GR in drug metabolism and guide the clinical intervention. Reference Bamberger CM, Bamberger AM, de Castro M and Chrousos GP (1995) Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 95:2435-2441. Bian HS, Ngo SY, Tan W, Wong CH, Boelsterli UA and Tan TM (2007) Induction of human sulfotransferase 1A3 (SULT1A3) by glucocorticoids. Life Sci 81:1659-1667. 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Sexism And Its Implications On Gender Roles - 1900 Words

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Gender Specific Slavery During The Period Of The Civil War

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Being a Successful Student free essay sample

The process of being a successful hybrid student. In order to explain the process of a successful hybrid student, the student must first define success. In defining success the student needs to determine what their goals are for the hybrid class. Success carries a different meaning depending on who it concerns. One students success could be receiving an A in the course, while another students meaning of success could be receiving Just enough to pass the course. After defining what success means to the student, the student should then establish a good time management plan.This is where the student takes time to analyze their schedule to prioritize other responsibilities as well as establish an effective balance between them all. Time management is extremely important in being a successful hybrid student, since most of the work and assignment is done outside of the traditional classroom environment. Once the student has defined what success means to them, determined their goals for the class, and established a good time management plan, the student then needs to have the discipline to follow through. We will write a custom essay sample on Being a Successful Student or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page Discipline Is the key to the overall outcome of he students success. Without discipline, a student can have many goals and plans of achieving those goals, but may loose focus along the way. The success of a hybrid student all defendants on the Individual student. What success means to the student Is the primary factor in the process. A good balance In time management will help the hybrid student to complete assignments on time. The last and most important step In being a successful hybrid student Is discipline. Discipline will keep you focus on your goals and plans for success, not only In the hybrid class but also In life.

Elektra Product Inc free essay sample

Elektra product decides to create a new product by pointing Barbara as their manufacturing head to responsible on it. Barbara accepts it as a compliment and starts to work with her team to make a great product. Barbara Russell, Elektras Vice President of Manufacturing, has been tasked by Martin Griffin, Elektras new President, to head one of the teams that will devise a plan to change Elektras management style from a traditional top-down firm to a de-centralized organization that emphasizes employee empowerment in the management process. She and her team did a good preparation until the day of presentation. Martin, who is her boss, interested with the ideas but he didn’t attend the meeting. Now, Barbara facing the problem to defending her ideas in front of other department head who are not agree with her ideas with many reason based on company data.. Solution Several objectives can come out as a solution for this problem. We will write a custom essay sample on Elektra Product Inc or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page One of the option is the company can restructured the department head or team leader to a new person who can give a hope to their subordinate by giving his/her hard work and ideas. Sometimes an old employee only has a narrow opinion by not accepting a new idea to improve the work flow inside the company. Another option is before Barbara come with the new ideas, the other department head should provide her historical data and information in order to make a decent product. And during creating the products, Barbara should involve the department head when she formulating the ideas before implementing to the new products. Question 1: How might top management have done a better job changing Elektra Products into a new kind of organization? What might they do now to get the empowerment process back on track? Note: Question 1 asks two questions; both must be answered in the response to Question 1. Response: Answer 1 Top management could have included the mid and lower level managers, and employees in the study teams. The study teams should have received instruction on the concept behind empowerment, and how the objective was to have employees at all levels taking responsibility for decision making, at that level, and accepting responsibility for the results. Answer 2 To get the program back on track, Mr. Griffin needs. 1. What theories about motivation underlie the switch from salary to commission pay? Solution: The theory of motivation to stimulate sales performance assumes money is a primary motivator. This form of motivation is based on content theories of motivation. With increased sales commissions, money can satisfy psychological needs, social needs, and self-esteem. Also, the expectancy and equity process theories of motivation can be applied to this situation. According to Expectancy theory, the employee is attracted to the reward being offered and believes he or she can put forth the effort necessary to achieve a level of performance that will lead to that reward (Daft Marcic, 2010). Commission pay is an extrinsic reward that will often increase performance by sales people. Equity theory relates to sales people being compensated for their level of effort, compared to other sales people and the compensation they receive for their level of work (Daft Marcic, 2010).

Garth Brooks - Fresh Horses free essay sample

I recently acquired a Garth Brooks box set and can honestly say it has some of the best music I have ever heard. Already an avid fan, I was not surprised by the superfluous amount of magnificent music, but one album in particular grabbed my attention: Fresh Horses. I have listened to it once a day for the past two months. It seems every time I listen, I find something new, inspiring and brilliant. Fresh Horses contains some of the most creative songwriting in recent country music, and Brooks co-wrote most of the songs. He manages to capture the meaning of each in his voice. One can hear the emotion in his tone, and he has a wide-range of vocal ability. Brooks sings effortlessly through the fast, old-fashioned songs like The Old Stuff and Rollin, then proves that he is one of the best classic country singers. Brooks also ventures into slower, more vocally demanding song like The Change. We will write a custom essay sample on Garth Brooks Fresh Horses or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page This is sung flawlessly and has a deep and meaningful message about continuing to do what is just and right in this world. But most important, the song is about making a change in yourself before trying to change the world. As one can tell, this song deals with intense emotion that Brooks portrays perfectly. This album is completely original, combining amazing producing with genius songwriting and flawless singing. Although I was already a Garth Brooks fan before I heard it, I was still surprised at his amazing talent. This album may be older, but it stands the test of time and continues to influence country artists today. If you are looking for an all-time great country album, Fresh Horses is it.