Just When You Thought You Understood Pharmacogenomics; Phamacoepigenomics, The New, New Frontier.

One of the interesting processes that occur in science is the examination of what we don’t understand and are only beginning to appreciate. Todays paper is an example of that process. As we discussed in class the authors are examining the hypothesis that attempts to relate the actions of various therapeutic compounds with the regulation of the flow of information coming out of the nucleus of the cell.

This is not a new concept, but it is only now that we have laboratory tools that will allow us to examine not just the sequence of the genome, but the individual expression state of the genes within the genome.

The authors provide a nice introduction in the summary:

“The term ‘‘Epigenetics” refers to DNA and chromatin modifications that persist from one cell division to the next, despite a lack of change in the underlying DNA sequence. The ‘‘epigenome” refers to the overall epigenetic state of a cell, and serves as an interface between the environment and the genome. The epi- genome is dynamic and responsive to environmental signals not only during development, but also throughout life; and it is becoming increasingly apparent that chemicals can cause changes in gene expression that persist long after exposure has ceased.”

First I would like you to write a working definition of the terms

  • epigenetics
  • epigenome
  • Phamacoepigenomics

Then look through the paper and find an example of a phamacoepigenomic phenomenon. You will probably have to look up at least one reference about the phenomenon, but remember the paper has the references to the data within the text, use these references and PubMed to look up a paper or two.

Once you have gone through the paper and the references write a summary of the phamacoepigenomic phenomenon, explaining why the authors think this is an epigenetic form of regulation.

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25 thoughts on “Just When You Thought You Understood Pharmacogenomics; Phamacoepigenomics, The New, New Frontier.

  1. Epigenetic can be defined as changes in the gene expression of an organism, more specifically it refers to the DNA and chromatin modification from one cell division to the next, and its persistence throughout an organism’s life. Epigenetic processes are caused by exposure to toxic agents in the environment and overuse of pharmaceutical drugs. The term epigenome can be defined as the overall epigenetic state of the genome. Pharmacoepigenomics refers to how pharmaceutical drugs can cause changes in the epigenome.

    The article provided a clear definition for the types of epigenetic processes that modern medicine and the environment can affect and gave sufficient examples to support the hypothesis that various agents can cause epigenetic changes directly targeting DNA methylation, acetylation, phosphorylation, ubiquitylation and sumolyation of histones, or indirectly targeting transcription factor activation or receptor expression. One example the article gave to support the hypothesis is the use of valproate, more commonly known as valproic acid or depakote. It is a therapeutic drug used to treat bipolar disorder, depression and epilepsy. Experiments in rats have shown the drug’s ability to act as a histone deacetylase inhibitor to alter chromatin structure, which cause severe side effects such as microvesicular steatosis and necrosis of the liver. Milutinvic, D’Alessio and Detich have also suggested in Carcinogenesis, that valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. The profiling data of valproate treated rats, demonstrated the drug’s ability to cause changes in gene expression associated with lipid, fatty acid, steroid metabolism and many more.

    I guess what the article is trying to say is that there is a whole other field in medicine that has yet been fully explored. Epigenetics is relevant to modern medicine and studying it will lead to advancement in numerous fields. However, certain pharmaceutical drugs, environmental agents, even thoughts or emotions can induce temporary, permanent or transgenerational epigenetic changes. It is such a scary fact to know that we have so many odds put against us and normal drugs that are used to treat common diseases have the potential to cause partial epigenetic etiologies, such as cancer, infertility, autoimmune disease and many more. It is discoveries like this that makes me question what is our purpose in getting treated? When we might face more severe problems after the treatment?

  2. The term epigenetics refer to the changes in gene expression in cells and organisms and these changes may persist through cell division and for the remainder of the cell’s or organism’s life. Epigenetic changes may arise due to misuse of certain drugs in specific treatment and/or the adverse effects of the drugs in accordance with the specific treatment applied. Wheras, “epigenome” refers to the overall epigenetic state of genome and pharmacoepigenomics is a new approach to pharmacology which reveals the adverse side-effects/changes of pharmaceutical drugs on epigenome.

    This particular research article strives to prove its hypothesis by scrutinizing various drugs and further extrapolating the side-effects of them based on gene/environment interaction. To attain a concrete standpoint, this article looks upon various epigenetic processes such as methylation of DNA, and acetylation, phosphorylation focusing primarily on direct and indirect effects of the pharmaceutical drugs. One such example includes chemotherapy in which patients experience neurological side-effects such as memory loss and cognitive dysfunction and sometimes seizures, vision loss and dementia. Although these symptoms were attributed to fatigue, depression and anxiety, modern research has revealed that these symptoms are the results of chemo therapy and thus contributes to fatal side effects. Additionally, chemotherapy drugs used to treat cancers were toxic to healthy brain cells and intercept extensive damage to normal body cells. This shows the “usefulness” of the chemo and its counterpart drugs. Pogribny, Rusyn, Beland performed an experiment on rodents in which they considered the similarities and differences in the epigenetic effects of genotoxic and non-genotoxic rodent liver carcinogens and the possible role of epigenetic changes in the casuality of tumor development. Since environmental agents are considered to be genotoxic, they interact with DNA directly causing mutations, leading to tumor formation. Therefore, it is likely that chemotherapy drugs cause epigenetic damage due to its genotoxic behavior.

    I feel that this article compiles all the research work in a single set to show the adverse effects of the drugs and also endeavors to reveal the best possible way to subside those medications in order to avoid the deleterious effects on an organism. However, when I read the paper for the first time, I was overwhelmed by the pessimism and negativity overhauled me after realizing the drugs which we use to treat for preliminary purposes seemed to comprise of multifarious side-effects. But I still enjoyed reading this paper because it helped me recognize the fact about various drugs and how the field of pharmacogenomic is expanding with new interventions. Not only, it accounts the drugs inside out, but also saves significant time, money, effort by eliminating potentially toxic drugs from developing.

  3. Epigenetic can be defined as a change in the chromosome that does not entirely affect the primary or basic structure of the DNA. The modification is carried on from one cell to another through cell division. It is often caused by an outside source, such as the environment and drugs. An epigenome is basically the genome, but in the epigenetic state. The field of pharmacology that studies how drugs cause epigenetic changes is called pharmacoepigenomics.
    This paper lists and discusses the various types of drugs that can cause epigenetic changes, such as DNA methylation, phosphorylation, ubiquiylation, sumolyation of histones, gene translocation, protein degradation, RNA transcription, and transposon activation. These changes in the gene can lead to side-effects, adverse effects and even common illnesses such as cancer, diabetes, Parkinson’s and Alzheimer’s disease, and sexual dysfunction. One example of the drugs that the authors mention is Combined Oral Contraceptive Pill (COCP) and synthetic estrogen, diethylstilbestrol (DES). The COCP is a pill that contains estrogen and progestin, which helps prevent fertility by preventing the women from ovulating. These sex steroids interact with receptors, and therefore, they cause indirect epigenetic effects. According to Panzer, COCP increases the level of androgen ovarian synthesis and Sex Hormone Binding Globulin (SHBG), which leads to sexual dysfunction. SHBG binds to the sex hormones and makes them useless. It causes epigenetic effect because even after the women has stopped using COCP, they were still experiencing high levels of SHBG. Diethylstilbestrol (DES) also causes epigenetic effects. Women who took DES have a higher risk of developing breast cancer. Children of women that took DES during pregnancy have a higher risk of cancer in the reproductive organs. This shows the transgenerational epigenetic effects of DES, especially since the daughters also have higher risk of developing breast cancer. DES is also linked to causing testicular abnormalities and prostate cancer in sons of women who took DES, and an uncommon cancer called clear cell adenocarcinoma in daughters. According to Kangaspeska, the breast cancer is produced due to the accelerated epigenetic changes in breast cancer cells.
    This paper proves that although these drugs help prevent and cure some diseases, they also can lead to long-term effects by altering the DNA. This is a bit scary. Who would have thought that the aftermath of taking a specific drug can be so life alternating? This paper makes me realize that there is still so much that we do not know and that we need to research about. This might lead to recalls of certain drugs and more testing before it can be sold to patients. Who knows what else we can discover about drugs and our body?

  4. The meaning of the word ‘’Epigenetics’’ changed through time. Today the term Epigenetics means changes in phenotype or gene expressions in cells or organism. Now epigenetic changes do not alter the DNA sequence, the affect the surroundings of the gene (Like enzymes, proteins…) and influence the transcription of the gene. These changes can remain in cells during cell division, and throughout the cells or organisms lifetime. Epigenomes is overall state of the epigenetic state of the genome. Phamacoepigenomics is the study of these genomes and their effects by employing microarray analyses of gene expression and methylation patterns so that we could better understand the long term side effects of drugs.
    One example of such epinogenetic effect is called ‘’Chemo brain’’. During chemotherapy patients frequently complain of neurological problems such as vision loss, memory loss, cognitive dysfunctions and seizures. And until recently this symptoms were explained through fatigue and depression because of the cancer diagnosis and treatment. A recent study showed that three common drugs used in cancer treatments were more toxic to healthy cells than to the cancer cells. A conducted experiment on mice which were exposed to a drug that is used for cancer treatments named 5-fluorouracil (5-FU) in the same doses as those used in patients, showed that after months of exposure ,oligodendrocytes, and dividing cells precursor cells from which they have generated, suffered such damage that after six months almost all of the cells have been destroyed.
    The usage of therapeutic drugs and its science is still relatively young, and it still needs improvements to reach its desired potential. Medical drugs beside they side effects still save and prolongs lives, we can argue about the slow advances in better understanding of certain drug effects but looking back half a century ago our understanding of this has extended significantly which just makes me look forward to new researches and discoveries.

  5. Fatima Taylor

    Epigenetics: The term refers to Chromatin and DNA modifications or heritable traits in cells and organisms that last throughout an organism’s cell divisions without a change to that organism’s underlying DNA sequence.
    Epigenome: The term refers to the overall epigenetic state of a cell and serves as a like between the cell’s genome and external environment.
    Pharmacoepigenomics: Analyses of gene expression and methylation patterns that can lead to a better understanding of the long term side effects to drugs. Also, as this applies to future epigenetic assays should be included in the safety assessment and regulation of all pharmaceutical drugs.
    Epigenetics is a fairly recent branch of science that is still very much in the research phase. This article poses several hypotheses, with evidence to support their claims in concerning epigenetic side effects induced by pharmaceuticals on the epigenome of the cell. These side effects include heart disease, neurological effects, cancer, obesity, diabetes, cognitive disorders, teratogens, as well as several other illnesses and disorders. One pharmacoepigenomic phenomenon that the paper discussed that I found to be interesting is the indirect teratogenic effects caused by drugs such as thalidomide and isotretinoin. It is not known by which mechanisms completely that these drugs cause birth defects but the author’s believe that they could interfere with normal controls of DNA methylation; an extremely crucial process. By interfering with this process, it results in abberant gene expression. Thalidomide is a sedative drug that pregnant women in Europe used during the 1960’s to help alleviate morning sickness. The birth defects in the babies may have been caused by heritable epigenetic defect; thalidomide may have interacted with specific proteins that produced a defect in the normal pattern of DNA methylation. After taking thalidomide, women began to give birth to babies with strange side effects such as pharcomelia, better known as flipper limb syndrome. Although it is unknown how thalidomide may have cause epigenetic affects, several hypothesis support this theory. Isoretinoin is a derivative of retinoic acid which is used in the treatment of severe acne. Isoretinoin has been known to carry a significant risk of producing teratogenic effects and pregnant women were discouraged against consumption of the drug. Isoretinoin acts as a successful acne treatment because is that it alters the DNA transcription process, while effectively decreasing the size of the sebaceous glands. The sebaceous glands secrete sebum, which causes skin to become oily, contributing the problem of acne. It also reduces keratinization of skin cells, which cause the sebaceous glands to become sticky, allowing the acnes bacterium to stick to the skin. Based on studies, isotretinoin is stated to carry a risk of around thirty-five percent of congenital malformation especially when consumed early in pregnancy. Birth defects range from external physical abnormalities of the face, eyes and ears; including facial dysmorphia, a cleft palate, micropinna of the ears and microphthalmia of the eyes. Several of these disorders affect the proper function of sight and hearing. It also produces damaging effects to the Central Nervous System including microcephaly, cerebellar malformation, hydrocephalus and issues with cranial nerve development. The author’s believe that this drug causes epigenetic defects because it causing an alteration in the DNA transcription process. This causes an alteration in gene expression and methylation processes by either direct or indirect effects.
    The paper I used was [48] Zhang

  6. This paper proposes that these epigenetic side effect may be among the causes for various issues like cancer, obesity, diabietes ,heart disease, and many others. So the paper suggests that studying the gene expression on a level of molecular biology may lead to a great understanding of these drug side effects and disease which they are believed to cause. They choose to coin this method of study : pharmacoepigenomics”. “Here we present the hypothesis that commonly-
    used pharmaceutical drugs can cause such persistent epigenetic changes. Drugs may alter epigenetic
    homeostasis by direct or indirect mechanisms. Direct effects may be caused by drugs which affect
    chromatin architecture or DNA methylation.” This is basically stating that certain drugs can affect our DNA. They can alter is by directly changing the structure of the chromatin or by how the methyl group is bound.
    “With more chronic exposure, cells adapt by an unknown hypothetical
    process that results in more permanent modifications to DNA methylation and chromatin
    structure, leading to enduring alteration of a given epigenetic network. Therefore, any epigenetic side effect
    caused by a drug may persist after the drug is discontinued.” The longer the druve is given with the epigenetic modifying tendencies the more permanent the alterations in chromatin structure and dna methylation will become. So in theory, even after a drug with epigenetic side effects is removed from the patiens discourse of treatment the side effects will continue .

    One phenom discussed in the paper was that of oral contraceptives: suggesting that over time usage of this method of low dose hormone therapy can cause mammary carcinoma later in life. This is due to “rapid epigenetic changes in the breast cancer cells”. Animal studies have shoe that these epigenetic effects show up in the next generation. The paper looked at 23 studies on the issue or oral contraceptive use and breast cancer- the over whelming majority (21) showed an increased risk of cancer. I took the liberty of looking up an article on PUBMED(Menopause. 2010 Feb 2. [Epub ahead of print]
    Estrogen therapy and risk of breast cancer in postmenopausal women: a case-control study and results of a multivariate analysis.
    Lumachi F, Frigo AC, Basso U, Tombolan V, Ermani M.)and found that the data was non conclusive. The study suggests that more models and subsets of research need to be looked into but IN GENERAL oral contraceptive usage (post menopausal) was not directly linked to breast cancer. I like this study because it is very recent March 2010 (ahead of print) however it is an Italian study and focused on post menopausal oral contraceptive usage. To be best informed it would merit one to look into a recent American study on the pre-menopausal usage or oral contraceptives. So I did that: I looked up on PUBMED “ premenopausal oral contraceptive usage and breast cancer” and many articles came up however the most recent article was from 1999 so I chose not to read it.
    Overall the idea of epigenetics seems very interesting and worthwhile for research. I am interested to see the field grow during my time as a student and hopefully one day as a professional.

  7. This article, “Just When You Thought You Understood Pharmacogenomics; Phamacoepigenomics, The New, New Frontier.” Mainly handles the concept of three terms, epigenetics, epigenome and a fairly new term, pharmacoepigenomics. The term epigenetics refers to the potentially long term changes in genes, often caused by gene/environment interactions. The term epigenome is the definition of epigenetics in a broader state; it takes into account the epigenetic conditions of the entire genome and the term pharmacoepigenomics refers to the relationship between pharmaceutical drugs and a genome.

    To support their hypothesis, which states that “commonly-used pharmaceutical drugs can cause persistent epigenetic changes, which can be manifested in the persistence of drug-induced adverse events” the authors provide various examples of drugs that have direct effects and indirect effects. The drugs that proved to have direct effects were hydralizine, procainamide, valproate and methotrexate and the drugs that proved to have indirect effects were thalidomide, isotretinoin, neuroleptics, SSRIs, ritalin, adderal, chemotherapeutic drugs, anesthetic drugs, synthetic estrogen, oral contraceptive drugs, chloroquine, floroquinolone, beta blockers, statins and cox-2 inhibitors. The two that stood out to me the most were the anesthetic drugs and the oral contraceptive drugs mainly because these are commonly used by a widespread of people globally that are unaware of the possibility of long term epigenetic side effects they may cause.

    The Combined Oral Contraceptive Pill (COCP) commonly known as Plan B or the Morning After Pill serves the purpose of preventing pregnancy after unprotected intercourse by disrupting the female hormone cycle natural processes. In slightly more detail the pill contains estrogen and progestin and research has shown that estrogen can in fact cause epigenetic changes. Research has also shown that COCP increases the risk of breast cancer in some women by almost 50% and that COCP elevates levels of Sex Hormone Binding Globulin (SHBG) which binds to hormones inhibiting them and also potentially causing sexual dysfunction. If this were temporary it may not be much of a problem to worry about but due to research showing that SHGB levels remaining at their elevated state even after discontinued use of the pill, the possibility of this being a long term or permanent epigenetic effect is in the realm of possibility.

    This paper did a wonderful job at getting the point across and I found it particularly interesting because they used examples of everyday drugs that I can relate to having used myself or I know somebody who has used them and could possibly have been affected in some of the ways this article discusses. It is almost an eye opener which some might almost be reluctant to accept because the article implies that everyday drugs that consumers might like to think is only having a positive effect on them may in fact being having a more negative long term effect on their epigenome. In some ways the article also implies that although it seems we have made it so far in science, we’ve actually only begun, that we have been looking at medicine in too narrow of a view, a view that needs to be broadened and that we have a long way to go. All in all this was the most interesting article I’ve read in the class so far.

  8. In this paper, the authors speak of a new hypothesis based around epigenetics. Epigenetics is the study of DNA and gene expression, and the changes in the expression due outside factors without affecting the actual DNA sequence. These changes often occur during cell division and specialization like when stem cells are turning into regular somatic cells but can also occur in regular cells throughout an organism’s lifespan. In epigenetics, the epigenome is studied. Like an organism’s genome, the epigenome is the overall gene expression and activity that the organism has. This specific paper chose to focus on a hypothesis that drugs promote epigenetic changes and these changes can cause the common side effects listed on medications or that they can cause long term changes which can lead to disease. Pharmacoepigenetics is the study of the changes that drugs are having on the DNA and investigating the long term and adverse effects of such changes.
    Pharmacoepigenomic phenomenons are certain areas such as drugs that are being studied in this new field that are said to have these changes occur. Since this is still a new field, not all drugs that scientists believe have this phenomenon have been studied. However, in the paper some drugs that scientists believe have epigenetic changes occur were mentioned. I think that this field is a new way of viewing medicine and with more research, can find alternative methods to reduce these epigenetic changes from occurring.
    One specific phenomenon mentioned in the paper was general anesthetics. There has been a recent concern that by using anesthetics, that the patient’s cognitive abilities could be effected beyond the time in which they are exposed to the anesthetic, and these effects could be permanent, especially with people of an older age. Research has shown that these general anesthetics are said to create a cycle of apoptosis, neuronal damage and also enhance protein misfolding and aggregation. With such side effects of using a general anesthetics, scientists are starting to believe there is a link between undergoing surgeries and the formation of neuronal degenerative disorders such as Alzheimer’s or Parkinson’s disease. In relation to the epigenetic changes, the use of anesthetics has shown a change in gene expression during use of the anesthetics, but after exposure to the anesthetic as well.
    I think that this new field of epigenetics is very interesting since it explains how there can be a link between these changes in the DNA and the formation of diseases and side effects. It can also explain why some people experience different side effects when on certain medications. With more research, this field has the potential to answer a lot of unanswered questions in medicine.

  9. The words “epigenetics”, “epigenome” and “Phamacoepigenomics” are the focuses of this article. With the prefix “epi”, meaning above or addition to, these words set the scene to the topic in question.
    Epigenetics refers to changes in gene expression in cells and living organisms that may persist through cell division and in some cases, the remainder of the organism’s life. There are no actual changes done to the actual genes, but actually, to the way the genes behave and well, express themselves due to environmental factors. An example of this is “cell differentiation” when the cells become specialized into their unique designations with the help of nutrients such as NGF.
    The epigenome is the overall state of the cell, and serves as the terminal between the actual genome and its environment. It is dynamic and responsive to the environment throughout all stages of life including development.
    We use the terms “epigenetics” and “epigenome “when discussing Phamacoepigenomics, the new approach to pharmacology where the understanding of the side effects of drugs can help in the future in the safety assessment of all pharmaceutical drugs.
    To understand the importance of Phamacoepigenomics, it is important to look into cases where the influence of the environment, in particular pharmaceutical drugs, caused epigenetic changes in the patient. Consider the example of psychiatric drugs.
    The brain, in simplest terms, is like a massive computer network that runs on the neural networks that can be prone to malfunctioning. In the process of trying to “repair” this dysfunction, there can be many other complications, such as the adverse side effects of drugs. Many see the side effects of such psychiatric drugs such as neuroleptics as an example of a phenomenon of phamacoepigenomics because of its adverse effects in patients who actually take this drug for the treatment of symptoms of schizophrenia. Long-term use of these kinds of drugs can cause drug-induced diseases such as Tardive Dyskenesia (DT), which causes a person to involuntarily spasm in areas such as the lips and in the eyes, and in some cases, other ligaments even after some time has elapsed between the discontinuation of the medication and the present. Although the etiology of TD is not well understood, the most likely cause is related to the epigenetic damage to the system that processes and uses neurotransmitter dopamine by neuroleptics.
    The main foundation of phamacoepigenomics is a very insightful one but at the same time, a very frightening thought. The common man uses pharmaceutical medication for the sole purpose of relieving everything from discomfort to pain in many areas of the body. He would never think twice of the consequences the drug can have on him until, in some cases, it is too late.

  10. Epigenetics has had many definitions over the years. Today it has a narrower meaning and is defined as changes in gene expression and gene regulation, which does not change the DNA sequence. This depends on environmental factors and heritable changes in cells and organisms. This can include long-term changes that have lasted for many generations, which is termed transgenerational changes. Epigenome refers to the study of the epigenetic changes and modifications as a single gene and whole gene. This can help us understand more about diseases and illnesses as well as about stem cells and evolution. Phamacoepigenomics is an approach to understand the effects of long term side effects using microarray analyses and gene expression. This will help us understand and improve the future of pharmaceutical drugs. For example, cancer patients complain about side effects such as memory and vision loss. It was found that these effects are a result of side effects from chemotherapy drugs. These drugs have more of an adverse effect on brain cells than cancer cells. The drugs are genotoxic and probably cause damages and alterations to the epigenome. For example, the drug tamoxifen is a drug used for the treatment of breast cancer. This drug has been found to cause epigenetic inactivation and modifications through tamoxifen-induced hepatocarcinogenesis.

  11. The definition of the word Epigenetics is the study of changes in phenotype or gene expression caused by a mechanism other than changes in the DNA sequence. These changes are not caused by any change in the DNA; instead non genetic factors cause the organisms genes to behave differently. These changes may remain in a cell for the remainder of the cells life, meaning after cell division, as well as last for multiple generations. The word Epigenome means the total epigenetic state of a cell. Phamacoepigenomics represent the new approach to pharmacology, which studies how pharmaceutical drugs cause changes in Epigenome.
    This article provided many examples to explain what Epigenetic changes occur in our cell’s DNA because of modern medicine or because of our environment. And these examples were sufficient to prove the hypothesis that pharmaceuticals are affecting “directly” and “indirectly”. Although they affect our DNA, they do not directly change its sequence, some ways our DNA is affected are: as methylation of DNA, and acetylation, phosphorylation, ubiquitylation, and sumolyation of histones; these are mostly direct. Some indirect effects are: transcription factor activation, receptor expression, etc. an example of a direct affecting drug given in the paper is hydralazine. Hydralazine is used to treat hypertension. This drug is known to have an epigenetic effect on DNA methylation. The inhibition of DNA methylation can trigger a lupus like autoimmune disease in the people who take this drug. Golbus, Maybaum Strahler, Hanash, Richardson andCornacchia are scientist who proved that when DNA methylation is inhibited, specifically 5-azacytidine, the T cells became autoreactive. And they also proved that hydralazine mimics as an inhibitor of DNA methylation thus inducing autoimmunity by making T cells autoreactive.
    This paper has given a new eye, one that can look at medicine in a new way, because although medicine may help me feel better I can no longer trust their effect on my body and its cells. Knowing that these effects may lead to more serious illnesses like cancer and infertility has made me think what do we really know about genes? But learning about a whole new field of pharmacology, Epigenetics, which is looking into more detail at the drugs side effects has also given new hope that someday people may fully understand our complex bodies.

  12. The term epigenetics can be defined as a change in a cell or organisms phenotype due to environmental factors which do not change the genotype. This change can either last through many cell divisions, through the organism or cells life, or through multiple generations. Epigenome can be defined as the total “epigenetic state of the genome.” Finally, phamacoepigenomics is the adverse effects a pharmaceutical drug can have on the genome of a cell or organism.

    The paper we read lists the different types of epigenitic processes and gives example of different drugs that can cause these epigenetic processes to occur.
    Hydralazine, procainamide, valproate, and methotrexate are direct effect. These “directly interfere with the normal controls of DNA methylation.” Drugs with indirect effects are thalidomide, isotretinoin, neuroleptics, SSRIs, Ritalin, adderall, chemotherapeutics, general anesthetics, synthetic estrogens, combined oral contraceptive pill, chloroquine, fluoroquinolone, beta-blockers, statins, and cox-2 inhibitors. These drugs bring about epigenetic changes by “interacting with a cell surface receptor, enzyme, or other protein.”

    One of the examples of a drug with an epigenetic effect given in the paper are beta-blockers. Beta-blockers are “used to treat hypertension and manage cardiac arrhythmias and give cardioprotection after myocardial infarction.” This paper talks about how a patients risk diabetes is increased especially when taking a diuretic as well. Is suggests that when beta-blockers are taken then can have the epigenetic effect on the body to accelerate the development of diabetes.

    The paper Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia shows that hyperglycemia can cause long-lasting activating epigenetic changes. Therefore since the beta-blockers can cause a change in glucose metabolism if there is a sustained amount of hyperglycemia one can be more likely to get diabetes. The paper New-onset diabetes and antihypertensive drugs shows that out of the patients with glucose intolerance there is a substantial amount that may become “aggravated by antihypertensive drug regimens based on…beta-blockers.”

    I think that people can be stuck in a very hard situation because their doctor says that they need to take a certain medicine to either treat or manage their disease but the side effects could end up putting them in a worse situation especially if they have epigenetic effect on their body. Epigenetic changes can be worse than regular side effects because they will continue even after the patient stops taking the medicine. This would also give them the worry about passing these certain diseases onto their offspring. Therefore more epigenetic research needs to be done before drugs are put on the market so we know the risks the patient could be taking. This would also give a better knowledge of whether or not a certain drug should even be on the market in the first place.

  13. This paper examines an up and coming field in medicine known as pharmacoepigenomics. This fairly new field examines how medicines effect DNA and gene expression. This field will become increasingly significant when trying to create new and safer drugs.

    Epigenetics is the study of the genetic changes that occur in the genome and/or gene expression other than the changes that occur in the underlying DNA sequence. These changes are brought on through environmental factors and as this paper examines, pharmaceutical drug. The changes cause the genes effected to be silenced, turned on, or express things differently.

    The epigenome is defined in the article as “the total epigenetic state of the cell.” The epigenome is the entire set of genetic changes in gene expression (and gene expression that has not been altered) in a cell or an organism.
    Pharmacoepigenomics is the study of how pharmaceutical drugs induce epigenetic changes that ultimately affect gene expression as well as how these changes may lead to other illnesses such as cancer and mental disorders.

    One of the pharmacoepigenomic phenomenons discussed in this paper involves the drugs hydralazine and procainamide. Hydralazine is a vasodilator, meaning it promotes dilation of blood vessels. It is prescribed to patients suffering from high blood pressure. Procainamide is an anti-arrhythmic sodium channel blocking medication, which means it prevents irregular heartbeat. Studies have found that these drugs have direct epigenetic side-effect since they interfere directly with DNA regulation and gene expression. These two drugs block DNA methylation and can often lead to a “lupus-like autoimmune disease.” DNA methylation is vital for an organism to develop and in cell differentiation. DNA methylation helps a cell remain differentiated (ex. A liver cell uses DNA methylation so it can “remember” that it is a liver cell). This process is also a basis for chromatin structure, which makes up our chromosomes.

    The lupus-like autoimmune disease is a result from a lack of DNA methylation which alters the expression of certain proteins which in turn leads to an immune response against the organism’s own cells. These drugs inhibit DNA methylation by interfering with the DNA methyltransferase reaction. This reaction is vital in order to copy DNA methylation patterns to daughter strands of DNA. Since this reaction is being inhibited, this explains why these epigenetic side effects can be inherited (daughter strands of DNA will also exhibit hypomethylation). Studies have also found that patients using these drugs develop antibodies against chromatin.

    The authors think this is an epigenetic effect since it interferes directly with gene expression. Disturbance of a DNA methylation reaction or interference with DNA methyltransferase would stem from a genetic change. In this case it is an epigenetic effect which interferes with these vital reactions and signal pathways because genes for certain enzymes and proteins become silenced or altered.

    This was a very interesting paper that was tedious to read through. People usually don’t think about the side effects the drugs they take can induce, especially epigenetic side effects. The idea that these changes can be inherited is scary. The field of pharmacoepigenomics should be incorporated into pharmaceutics in order to produce new and innovative drugs that pose less of a risk of causing epigenetic side effects.

  14. The development of pharmacoepigenomics opens up new a way of approaching the development of drugs and their effects on gene expression and cell function. The study of how drugs such as thalidomide affect the cell gives us more of an insight of how the alterations of gene expression can cause huge effects on the function of the cell. The study of epigenetics reveals new information on cell differentiation and the factors that contribute to it, and also help in the field of pharmacoepigenomics.
    Epigenomics is the study of gene expression that can be caused by environmental changes and cell differentiation and how different factors of the body can alter it. The structure of a cells chromatin determines its function for whatever type of cell it may be. The epigenome is the genes that are expressed for the type of cell it is. The chromatin structure and the histones play a huge part in the expression and silencing of genes. The understanding of the expression of certain genes in the chromatin can help the study of pharmacoepigenomics and produce drugs that can help stop cancerous cells from further developing or other unwanted malfunctions in the cell due to gene expression.
    Pharmacoepigenomics also points out the flaws in current medications that cause effects more harmful then the effects desired. An example of such implications is the cognitive dysfunctions and protein malformation effects of anesthetics. The use of anesthetics during surgical procedures insures precision and comfort during surgery however, the after effects can prove to be detrimental. The effects of anesthetics can cause protein malformation and aggregation. Apoptosis also occurs which can lead to a buildup of beta proteins, neuronal damage and cognitive dysfunction.
    The study of epigenomics can help regulate the handling of medications. The side effects of different medications can now be studied while also learning how certain chemicals effect gene expression that cause such side effects. The effects of drugs on the chromatin structure and histone tail methylation and acytlation can be taken into more consideration since it has been proven that long term changes in gene expression can occur after using medications.

  15. The word epigenetics has had many definitions that have changed over time. Epigenetics refers to the study of cell differentiation and genes of cells that change the DNA sequence and expression; which can be brought on by factors such as pharmaceutical drugs. The epigenome is “the total epigenetic state of the cell” which means it is all the changes in a cells gene expression and alterations. Pharmacoepigenomics is the study of pharmaceutical drugs that cause changes to occur in gene expression and cause diseases.
    While epigenetic processes are needed for organisms to function, they can occur inappropriately and have undesired effects such as DNA mehylation, acetlyation, phosphorylation, alternative RNA splicing, protein degradation, etc. One phenomenon described in the paper is general anesthetics. Even though these drugs have been improved by technology there is concern that using them, may affect a person’s cognitive abilities after exposure, and it could be permanent. Studies have also shown that anesthetics can even boost protein misfoldings, and aggregation, causing changes in genes and proteins. They believe there may be a connection with neurodegenerative disorders like Alzheimer’s or Parkinson’s disease with anesthetics during surgeries. Fodale V, Santamaria LB, Schifilliti D, and Mandal PK agree, with the help of in vitro spectroscopy done on anesthetics, there is an increase in the risk of developing cognitive disfunction due to the uncontrolled production of the amloyid beta peptide, especially to elderly patients.
    The paper was pretty clear in describing epigenetics and the effects that drugs can cause. I also liked how they used examples of some common drugs, to show their effects, so it would be easier for the readers to understand and relate to. This is a great field to continue research and make progress in because I think it is important to know the side effects and changes drugs can have on our genome.

  16. Epigenetics is a term whose definition has broadly changed from the time Waddington first came up with it in 1942. In simplest terms, epigenetics is the modification of a DNA strand without a change of the underlying DNA sequence. Waddington discovers how a cell differentiates based off of their surroundings to interact and form a different cell type. These changes often occur during cell division or replication such as when stem cells are formed or translated into somatic cells. Within epigenetics, the epigenome is studied. The epigenome is studied as the overall state of the cell between the actual genome and their environmental surroundings. Pharmacoepigenomics is the new approach to pharmacology to study the changes certain specific drugs have on epigenomes rather than just genomes. Certain epigenetic processes have been discovered such as methylation of DNA, acetylation, phosphylation, and sumolyation of histones and these are critical to the function of organisms. Among other phenomena’s discussed in the article, one that stuck out the most to me was oral contraceptives and their effect on the mammary carcinoma later on in life. This article thoroughly examines the way certain drugs affect specific cell differentiation throughout a cells lifetime. It further proves that there is plenty of room for expansion in the medical field that we have not further explored yet. With our growing technological advances, it will soon be possible to fully understand the depths of the pharmacoepigenomics world.

  17. This paper “Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology” mainly discusses the understanding of three terms, epigenetics, epigenome, and pharmcoepigenomics. The term epigenetics refers to DNA and chromatin modifications that is noticeable in all cell divisions without an underlying change in the DNA sequence. Toxic agents and pharmaceutical drugs can be one of the reasons for an epigenetic process to occur. The term ‘‘epigenome” refers to the overall epigenetic state of a cell, and serves as an interface between the environment and the genome. Pharmacoepigenomics is the branch of pharmacology that refers to how pharmaceutical drugs can cause changes in the epigenome.

    The study of epigenetics is a fairly new branch of science which hasn’t been explored into as much as it should. Many pharmacological agents can cause epigenetic changes such as the (COCP) Combined Oral Contraceptive Pill, synthetic estrogen, and diethylstilbestrol These drugs can cause changes in the gene expression that can lead to adverse effects such as cancer, diabetes, Parkinson’s and Alzheimer’s disease, and sexual dysfunction. For example COCP causes sexual dysfunction because it stimulates a chemical known as Sex Hormone Binding Globulin (SHBG) which binds to sex hormones rendering them useless and overall killing sexual functionality. ” Science Direct Volume 73, Issue 5, November 2009, Pages 770-780″.
    Diethylstilbestrol causes epigenetic effects developing breast cancer in women who have took it.

    This paper in general helped discuss the underlying issues of pharmaceutical agents and their adverse affects on our genome. Pharmacoepigenomics is still a fairly young branch of sicence and there is a lot of research to be done. Progress is being made none the less.

  18. Epigenetics is the study of the changes that happen in the gene expression/function with no change to the DNA sequence. An example of these changes include

    environmental changes that effect the gene function. These changes can have its effect on the cell for as long as the cells life span or even for multiple generations. The

    term epigenome is like that of the genome, except as the genome is to the DNA sequence, the epigenome is to the epigenetic changes. It is the changes to the gene

    expression as a whole, the entire change to the gene function without any adjustment to the DNA sequence. Phamacoepigenomics to my understanding is the study of

    how drugs cause and effect epigenetic changes. The study of how pharmaceutical drugs can cause/effect the changes of a genome.

    An example of phamacoepigenomic phenomenon that is mentioned in this article is that of the Combined Oral Contraceptive Pill also known as (COCP) and the

    Morning After Pill or Plan B. This pill is made up of estrogen and progestin and is to be taken orally; it inhibits fertility in women you’ve had unprotected sex or

    contraceptive failure one or more times in the last 72 hours or 3 days, and you don’t want to become pregnant. What this pill does is effect the female the fertility

    cycle and in fact causes epigenetic changes. The article states that “Many other adverse associations have been identified in DES-exposed women and their
    offspring, and animal studies have shown effects in the next generation(grandchildren), a clear demonstration of transgenerational epigenetic effects [144,145].” Which

    in according to my working definition of epigenetics, is an obvious example of epigenetics; a change in the genetic function, which lasted into generations. Estrogen

    also showed an epigenetic changes in breast cancer cells, causes sexual dysfunction, effects bone health, weight gain, depression, etc… The Morning After Pill is a

    perfect example of a pharmacoepigenomic phenomenon.

    This article at first glance was not appealing, but after reading it I found it pretty interesting. It’s intriguing because I learned about something so common like the Plan

    B pill into detail. In addition I learned about drugs that are used for hypertension and the behind the scenes of what such anesthetics do. It was informational, a little

    tedious, but still interesting. Definitely better than last weeks article!

  19. Epigenetics is defined as changes in the expression of genes in an organism or a cell, and it also refers to DNA and chromatin modifications from one cell division to the next, despite changes in the DNA sequence. As the word indicates, “Epigenome” is parallel to the word “genome”, and is used to describe the overall epigenetic state of the genome. Similarly, epigenomics is denoted from genomics, and it is the study of epigenetic modifications at a much larger scale, thus Pharmacoepigenomics is the study of drug effects on epigeneic states and how pharmaceutical drugs can cause such persistent epigenetic changes.
    Pharmaceutical drugs may disrupt epigenetic homeostasis by direct or indirect mechanisms. Direct effects are caused by drugs that target changes in DNA methylation which results in aberrant gene expression. Indirect effects are caused by changes in the surface receptor of cells which inhibits or alters expression of the receptors thereby influencing expression of growth factors, ion channels, transcription factors resulting in changed epigenetic homeostasis. Furthermore, cells are able to adapt to chronic exposure of changes in cellular processes thereby taking in altered expression of a given epigenetic condition resulting in permanent modifications to DNA methylation and chromatin architecture long after exposure has been ceased. One example of a pharmacoepigenomic phenomenon is “Chemo-Brain”, or the symptoms manifested after administration of chemotherapy drugs on a patient. Patients diagnosed with cancer experience side-effects which were often attributed to depression, fatigue, and anxiety due to stress related to cancer diagnosis. Surprisingly, it is becoming considerably recognized that these symptoms are actually derived from side-effects of chemotherapy. One experiment was performed, in which mice were exposed to 5-fluorouracil (5-FU) in amounts correlating to doses given to actual cancer patients, and after months of exposure to this drug, the dividing cells were adversely affected and progressively worsened as all of the cells were destroyed after six months. Myelinated tracts and the CNS were damaged, which was associated with altered gene expression. In addition, consistent use of chemotherapeutics led to the emergence of secondary cancers comparable to the original already under treatment. Also, chemotherapy drugs are known to exert genotoxic effects which cause epigenetic modifications. As an example, rats treated with Tamoxifen, a non-steroidal anti-estrogen, were found to be tamoxifen-induced and had hepatic tumors as a result of tamoxifen-DNA adducts. This mechanism contains an epigenetic component and it has demonstrated effects such as epigenetic inactivation of estrogenic responses, permanent chromatin remodeling, and changes in expression of microRNA. Thus, it can be concluded that tamoxifen induced effects are apparent in human cells which can cause modifications in epigenetic homeostasis. Obviously, “Chemo-brain” is one example of epigenetic form of regulation because the modifications were associated with drug-induced effects which were supposed to influence expression of DNA methylation and promote epigenetic homeostasis, but instead, this mechanism is known to exert genotoxic carcinogenesis which can prevent further treatment and complicate the conditions of patients by affecting epigenetic alterations.

  20. In this paper “epigenetic side effects of common pharmaceuticals” introduces a new topic in the pharmacogenetic field. The prefix “Epi” means above or in addition to something; the term “epigenetics” is relatively connects with the study of human genetic makeup. It is the change of the phenotype of the individual due to the exposure of certain biological or chemical materials. “Epigenome” refers to the overall epigenetic state of a cell. The pharmacoepigenomic is a new approach in pharmacology to investigate the impact of certain drugs on the phenotype of the individuals. Epigenetic change is not the change on DNA and chromatin formation but it is influenced by the environmental factors such as drugs or other chemical therapies. Some types of epigenetics processes have been identified such as methylation of DNA, and acetylation, phosphorylation, ubiquitylation, and sumolyation of histones.
    One phamacoepigenomic phenomenon that explained in this paper is general anesthetics. Millions of people are undergoing surgery every day, the most common anesthesia is the inhaled anesthesia. The general anesthesia has a growing concern that it might affect the patient’s cognitive abilities after the surgery especially for the elders. The scientists find useful evidences to prove that general anesthetics can cause the cycle of apoptosis, neuronal damage and can also enhance protein misfolding and aggregation. They also proposed a possible linkage between the anesthetic-induced neuronal injuries could cause Alzheimer’s or Parkinson’s diseases. As relation to epigenetic, the general anesthesia can also cause a small change in both gene and protein expressions during or after the exposure of anesthesia.
    I guess this paper is trying to show us the other outside factors that can affect the expressions of our genes. Many frequently used pharmaceutical drugs and practices may cause severe epigenetic changes. This article improved my knowledge on another new field of pharmacology, I come to understand that various types of drugs can actually cause serious side-effects after consuming. How can this problem be resolved? It might take some time for the scientists to go more depth into the problem by studying the specific side-effects and do more testing before it can be sold to the patients.

  21. In this article, it discuses the many variations of a newfound genetic study called Epigenetics. The authors within this article state that epigenetics is a process that refers to the changes in gene expression and organisms. It is the study of mechanisms of temporal and spatial control of gene activity during the development of complex organisms. It has the potential of playing such a vital role in understanding biological phenomenons such as stem cells, nuclear transfusion, aging, etc. The term known as the epigenome refers to the overall epigenetic state of a cell and serves as an interface between the environment and genome. It is dynamic and responsive to environmental signals not only during development but also throughout life. Pharmacoepigenomics allow for the discovery of potential untoward effects of drugs early in the drug development program and might save significant time, effort, money, and even lives by eliminating potentially toxic drugs from the development pipeline.

    Within the article, one of the pharmacogenomic phenomenons involves the mechanisms behind chemotherapeutics. In this article, it states that most cancer patients that undergo chemotherapy usually complain of neurological side effects. It was through the process of epigenetics that the toxicity of chemotherapy within the gene expression of brain cells was discovered. These “genetoxins” often cause epigenetic alterations that can unfortunately result in memory loss, seizures, depression and cognitive dysfunction. While utilizing the PubMed search engine, I also came across another article that supports the fact that pharmacoepigenomics plays a vital role in comprehending chemotherapy. This article was entitled “Cancer epigenomics: implications of DNA methylation in personalized cancer therapy.” The authors of this article researched how pharmacoepigenomics awaits the advent of genome-wide analysis of DNA methylation. A DNA methylation that tends to become a more distinct characteristic when chemotherapy is utilized.
    I believe this article was very important because it informs people how there are better methods available for making therapeutic drugs not only effective but safe. It gives people within the medical profession the chance to reevaluate the various drugs that are available to society in order to provide better therapeutic quality and awareness. One of the most interesting articles that we have read so far because it was an informative and enjoyable read.

  22. Epigenetics is defined as the changes in phenotype and gene expression. It refers to as the alterations of DNA and chromatin that continues on in cell divisions without the change in DNA sequence but surprisingly they cause changes in other organelles and molecules such as proteins and transcription molecules. The epigenome refers to the overall epigenetic state of the cell. It is the state in which epigenetics is taking place and acts as an interface in which it can be responsive to environmental signals not only in development but throughout life. Phamacoepigenomics refers to a possible new field of pharmacology in which epigenetic side-effects of pharmaceutical drugs can be studied through microarray analyses of gene expression and methylation patterns to help better understand long term side-effects of pharmaceutical drugs.

    Epigenetics seemed to be a new branching of pharmocogenics as they involve the realization of long term side-effects of pharmaceutical drugs which have been ignored or not put much attention on. These side-effects are harmful and life-threatening as some of which are heart disease, cancer, neurological and cognitive disorders, obesity, diabetes, infertility, and sexual dysfunction. One phenomenon discussed in this paper that I thought to be very compelling was the usage of drugs such as neuroleptics. Neuroleptics is a medication used to treat symptoms of schizophrenia by blocking dopamine receptors. It is found that the long term side-effects of these drugs can causes an iatrogenic disease called “Tardive Dyskinesia (TD)”. TD is termed as the involuntary repetitive movements such as tongue protrusion, grimacing, puckering of lips and etc. Rapid twitching of body parts such as arms and legs may occur as well and are deemed irreversible. It’s interesting to see that although TD has existed for over five decades and that its causes and etiology is very little understood. Scientists deemed TD as an epigenetic form of regulation from the fact that the drug uses the neurotransmitter dopamine for its activities. Neuroleptics have been proven to act primarily on dopamine as older neuroleptics that have greater affinity for dopamine D2 receptors seemed to cause higher risk of TD. The most convincing hypothesis for the etiology of TD is that it results from “neuroleptic-induced dopamine supersensitivity in the
    nigrostriatal pathway, with gene expression of the D2 dopamine receptor being most affected”. This means that the usage of neuroleptic to treat TD causes sensitivity within the nigrostriatal pathway which for some reason makes D2 Dopamine most vulnerable to being affected. Evidence shows that between-group comparisons that those treated with conventional neuroleptics instead of atypical neuroleptics were more prone to TD and D2 hypersensitivity is supported by dose-response relationship and withdrawal effects studied on animals, D2 agonists and antagonists, and genetic polymorphism studies. The reasons for the super sensitivity of neural pathways and the irreversibility are yet unknown. This shows that there needs to be more research and studies done to confirm any hypotheses. This new field of epigenetics seems to be very compelling as it shows how pharmaceutical drugs may cause DNA modifications and form diseases and long term side-effects. The deeper you go into epigenetics the line between diseases and medication may get blurred as it may suggest that gene expression is the cause of it all. Some people experience different side-effects with certain medications and now certain medications cause certain diseases based on genes. It just goes to show there needs to be more research done to fully understand how our bodies work if we want personalized medicine to work.

  23. Antonei B. Csoka and Moshe Szyf define “epigenetics” as DNA and chromatin modifications that persist from one cell division to the other without changing the sequence of the DNA. The “epigenome” serves as an interface between the environment and the genome because it is dynamic and responsive to the environmental signals during development and throughout life. It also refers to the overall epigenetic state of the genome that gives signals or regulates the amount of certain proteins or substance being made.
    The environment is not the only factor causing changes in gene expression of an organism; chemicals like those of pharmaceutical drugs are also causing these changes permanently. In other words, the epigenetic homeostasis has persistently changed for the organism after the consistent use of any pharmaceutical drugs. These epigenetic changes are categorized into “direct” and “indirect” effects to the organism in which the direct effect influences the DNA methylation and/or chromatin architecture whereas indirect effects influence the signaling pathways which can lead to alteration of transcription factor activity at gene promoters. This indirect change will ultimately change the expression of receptors, signaling molecules, and most importantly, other proteins that alter genetic regulatory circuits. Even after the drug is no longer used, the side-effects will remain because the body has gained a permanent genetic homeostasis to this drug that changed the way the body functions, for good. This research paper proposes that the epigenetic side-effects after using pharmaceuticals can cause heart diseases and many other abnormalities.
    “Pharmacoepigenomics” is now considered to be a step ahead of Pharmacogenomics and may also be more beneficial in the field of pharmacogenomics. This field is considered more useful because it is probing the genome and it’s intricacies through microarray analyses of gene expression and by studying methylation patterns that will introduce better knowledge of the side-effects that result from the drugs. The use of epigenetic assays may also be used as a “safety assessment” for pharmaceutical drugs. Through certain treatments on cancer patients, enzyme activity was also altered which also influenced the DNA methylation patterns which added more knowledge to the pharmacoepigenetic field instead of just the pharmacogenetic field.
    As stated above, as well as in the introduction of “Epigentic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology”, epigenetics is has to do with changes in gene expression that can remain through cell division or through life. These changes can become ‘transgenerational’ and the expression of genes is different, not the underlying DNA sequence. One of the examples used for pharmacoepigenetic phenomenon that I have had some experience with is cell differentiation. In cell differentiation, the cell, like a zygote, goes through multiple cell divisions into many cell types such as neurons, epithelial cells…etc by the turning on and off of certain genes. In the act of dividing cells, only some the epigenetic genes are transferred to the next generation and can, therefore, be expressed while others are permanently silenced in other replicated cells. I looked further into the two sources that referred to this phenomenon (Surani MA, Hayashi K, Hajkova P. Genetic and epigenetic regulators of pluripotency. Cell 2007;128:747–62.and Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 2007;447:425–32.), which explains how methylation of DNA can cause long-term DNA silencing of the unneeded somatic cells and specification of germ cells. But when there is a need to re-express the gene there is a permanent erasure of the epigenetic modification.

    I think the authors believe that these phenomenons are epigenetic forms of regulation because they explain how cells control the expression of genes by either turning the genes on and off or permanently influencing the modification and expression of genes by using certain drugs in pharmaceuticals. Overall, the action of silencing or turning on certain genes, due to either environmental changes or the use of certain pharmaceuticals, induce epigenetic changes by contacting any of the entities involved in gene expression (surface receptors, enzymes, proteins…etc). This would ultimately “alter expression of said receptors, growth factors, ion channels, structural molecules, or transcription factors and finally subsequently alters cellular homeostasis. If chronic, this persistently altered cellular gestalt induces a secondary change in DNA methylation by a heretofore unknown cellular feedback mechanism resulting in a changed epigenetic homeostasis.”

  24. “Epigenetics” is the cell variation without changes in the DNA sequence. The cell can be affected directly or indirectly by the drugs or environment factors. Not including alteration of genetic code, DNA methylation and acetylation, histone modification, chromatin remodeling, phosporylation, and ubiquitylation obstruct normal cell regulatory functions; these properties can be passed onto the next generation.
    “epigenome” is an epigenetic state of a cell and it serves as a massager between the environment and the genome. For example, the genome produces the necessary proteins, however it does not know how much the environment needs the proteins. In this situation, the epigenome helps to let the genome know how much protein is needed for the environment. On the other hand, when the environment has enough proteins and does not need anymore, the epigenome lets the genome know when to stop producing it. In other words, the epigenome takes charge of turning genes on or off for producing proteins. Epigenome has a charge of the gene expression. The gene expression is regulated by two most well known facts that DNA methylation and histone modification. DNA methylation is processing of methyl groups attach to specific places the backbone of DNA and it interfaces the gene and environment. Indirectly, histone modification switched gene on or off by loosing or tightening of histone loops. When the histone loops are loosened, a hidden gene in between the histone will be active. In other side, tightened histone loops mean dormant state of gene. However, this system can be destroyed by drugs, outside environmental factors that cause the malfunction of the cell, serious disease, and behavioral effects. In the past, the scientists believed only the wrong DNA sequence brings disorder of cell or organisms, like causing Alzheimer’s disease. However, scientists have now found that variation in cells or organisms are also affected by chemicals and environments. Pharmacologists, especially, focus on epigenetics because the drugs for major diseases change the normality of the cells. Therefore, the word “Pharmacoepigenomis” comes from a new aspect of pharmacology study of epigenetics. In pharmacology, epigenetics is an important subject because the scientists can avoid the side effects of the specific drugs and conversely, they can cure the major diseases such as cancer by stopping the reproduction of mutant genes.
    One of the examples of epigenetic phenomenon in this article is the isotretinoin (a 13-cis-retinoic-acid). This agent is using for severe acne and prevention and treatment for skin cancer. One of major usage of the isotretinoin is to get rid of comedones (blackheads) by change gene expression; it makes decreasing size and outputting of sebaceous glands that gives no more lumps. However, this agent has scary teratogenic effects on craniofacial, cardiovascular, cerebral, and central nerve system. The adverse effects are dryness of skin, hyperlipidaemia, ocular problems, and psychiatric disorder. Even if the patient stops to use isotretinoin, it gives epigenetic effects; one of them is alopecia. Moreover, it affects brain and central nervous system too. Normally, the base line for malformation of this agent is 3-5%; however, in pregnant women 30% of malformation rate is observed.
    After I read this paper, I felt scary for taking medicine, which would be affecting my cell or organism eventually. To conquer disease, people have to take certain medicine, at the same time, people suffer the side-effects. Like in my example, for preventing comedones, I do not want to use isotretinoin because I may be lost my healthy body for erasing my blackheads on my nose. I believe that epigenetic is important study for human health. For pharmacoepigenomics, it is must to have studying subject for preventing adverse effect of drugs. So far, the lack of information of medicine causes additional malformation of cells and organisms. By studying epigenetics, the scientists would make less harmful drugs. Reversely, the scientists use the side effects to suppress the cancer cells like controlling DNA methylation of cancer cell.

  25. The term Epigenetic is the blend of two words “genetics” and “epigenesis.” Epigenesis refers to the heritable traits that does not affect the DNA sequences of a cell or organism. Thus Epigenetic is the term used to describe the changes in gene expressions in cells without a change of DNA sequence. The agents of Epigenetic changes can be pesticide, smoking, hormones, radioactivity, and medical drugs. Similar to genome, the epigenome refers to the overall epigenetic state of the genome. Other word, it’s all the changes in gene expressions in the cell or organism. Phamacoepigenomic is a new approach that analyze these changed gene expressions which will lead to a better understanding of the long-term side-effects of drugs in particular.
    This article brings out this sort of hidden area in research that is yet to be explored. Although it is commonly known that all medicines have side-effect but what need to be brought under the light is that these side effects might not just appear while taking the medicine. They might cause a change in the genes long after they were taken and persist for a long time. The article hypothesizes this notion and therefore experiment with certain drugs that are known to cause epigenetic changes : Hydralazine and procainamide that inhibit DNA, Methotrexate, that alters methionine synthesis, drug resistance, and General anesthetics that result in Cognitive dysfunction, Alzheimer’s and Parkinson’s disease.
    Although we are all familiar with general anesthesia and it’s temporary influence on the patient’s conscious, this article goes to find other long term side-effects of these drugs. They can influence the cognitive abilities of the patients long after the surgery and even permanently, especially if the patients are old. They have been found to cause apoptosis, neuronal damage and durable cognitive dysfunction. Recent studies have shown that anesthetics can also increase the rate of protein misfolding and aggregation. More surprisingly, the ratio of patients having Alzheimer’s disease to having a previous surgery is 1.7, revealing a link between anesthetics and Alzheimer’s. Anesthetics are also known to cause substantial
    changes in gene and protein expressions. After exposure to isoflurane for a short time, many changes were visible in genetic control in the amygdala and it persisted up to days after exposure. This proves that recovery of the brain from anesthesia was slower than in general.
    The main idea of this research paper was to bring forward this new field called “epigenetic” which is expected to have a profound impact in better understanding the long-term side-effects of drugs. And this impact “may be equal to or greater than that of pharmacogenetics.”

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