subject: How Medication Can Change The Expression of Genes [print this page] The Basics of Cells, Genomes, Genes and DNA:
Every person's body is made up of many miniature cells that basically resemble chicken eggs. A cells "shell" is its outer membrane, the "egg yolk" its nucleus, the "yolk membrane" is the nuclear membrane and the "egg white" is the cytoplasm. In the cytoplasm are organelles (workers) which perform various functions for the cell, examples of which are mitochondria and ribosomes. Within the cell's nucleus numerous linked genes are coiled to form chromatin and are further packaged into chromosomes. The human genome refers to the entire collection of genes within a human cell. Cells can divide by replicating its DNA and cytoplasm allowing us to grow or repair damaged cells when we are injured.
Genes consist of deoxyribonucleic acids (DNA), made of nucleotides, which is responsible for the overall appearance of a person[1]. In the central dogma of biological sciences DNA is a coded message that is copied by mRNA (messenger ribonucleic acid) and transported out of the nucleus into the cytoplasm. Ribosomes, the cell's printing press, then attach to the mRNA allowing tRNA (transfer RNA) to bring amino acids corresponding to the coded message. The coded message is uncoded as the ribosome translocates or moves along the mRNA. The resulting amino acid string folds to form a protein. Hormones, enzymes, and antibodies are some examples of proteins.
What is Epigenetics?
One trigger behind the central dogma is epigenetics. The term "epigenetics" was first used in the 1940s, and means "above the genome"[2]. This concept entails that certain factors have the ability to make DNA undergo methylation (addition of a methyl group i.e. -CH3) or to cause chromatin modification. These alterations allow genes to be turned on or off. By turning a gene on its message will be expressed as a protein, if the gene is turned off it won't be expressed [2]. Scientists believe that epigenetics can explain why people age and, in the future, help prevent diseases [3]. Illnesses
The factors that can alter one's epigenetic status are food, environment, social influences, taking drugs or medications and even low levels of radiation from computed tomography (CT) scans [4]. Studies have found abnormal epigenetic changes in cancer cells associated with excessive methylation of tumour suppressing genes, which essentially turns off the genes that are responsible for controlling cell division[5]. The chromatin is changed via post-translational modifications such as acetylation (adding an acetyl group i.e. COCH3), phosphorylation (adding a phosphate group i.e. PO4-) and ubiquitination (adding ubiquitin, a small acidic protein) of histone proteins in cancer cells [6, 7].
Drugs have the potential to cause epigenetic changes and the following diseases have been linked to drugs: heart disease, neurological pathologies, diabetes, obesity, leukemia, and infertility. Most epigenetic changes are reversible[3], but continuous use of these drugs can lead to permanent changes that can be passed onto future generations. Pharmaceutical products that are currently on the market and cause these effects include anticancer drugs such as tamoxifen and methotrexate, antidepressants, some medications for heart disease and hypertension, some anti-inflammatory drugs, and statins or cholesterol-lowering medications [8].
Drugs and Epigenetics:
Our understanding of the epigenetics process can help us create better drugs for treating or even preventing disease. This concept is known as epigenetic therapy[8]. Vidaza and Dacogen are drugs that act on the epigenetics of cells and were approved for the treatment of myelodysplastic syndromes. These drugs are unable to target cancer cells only and harm other cells in the body, causing many side effects.
Vidaza works by inhibiting DNA methylation, resulting in hypomethylation of the DNA and direct toxicity to cancerous cells [10]. Through the same mechanism of action Vidaza promotes the maturation of healthy cells. Vidaza is contraindicated in patients with advanced malignant hepatic tumours[11].
Dacogen(decitabine) is an analogue of the natural nucleoside deoxycytidine and inhibits the action of an enzyme responsible for hypermethylation, DNA methyltransferases, by adding a phosphate group to it. The use of Dacogen has the potential to restore the normal functioning of genes in cancerous cells, reversing their uncontrolled differentiation [12].
Epigenetics in South Africa
In 2007 the National Institute of Health (NIH) created "The Roadmap for Medical Research's Epigenomics Program" consisting of various institutions which aim to "work together to understand epigenetics and how it affects human health and disease" according to Nora D. Volkow, M.D, the Director of the National Institute on Drug Abuse. On the 17th of September 2009 the NIH announced that funding will be allocated to studies related to epigenetics and illnesses such as tumour development, hardening of arteries, autism, glaucoma, asthma, aging and abnormal growth and development [13]. With the financial support that research institutions are now obtaining and with the right enthusiasm we can expect South Africa to become a pioneer in this field of research.
References
Lamb, R. (2010). How Epigenetics Works. Available: http://science.howstuffworks.com/environmental/life/genetic/epigenetics.htm. Date accessed: 10-08-2010.
Lamb, R. 2010. DNA may provide a genetic plan for you, but various factors affect how that plan will be expressed. Available: http://science.howstuffworks.com/environmental/life/genetic/epigenetics1.htm. Retrieved: 10-08-2010.
Anon. (2010) Epigenetic Therapy. Available: http://www.antiagingdoctor.co.za/?p=225 Date accessed: 10-08-2010.
American College of Radiology / American Roentgen Ray Society. (2010). Epigenetics could help researchers determine any risks associated with low-dose radiation.Retrieved August 11, 2010, from http://www.sciencedaily.com/releases/2010/02/100201091628.htm
Lawrence, E. (2005) Henderson's Dictionary of Biology, 5th Edition. Pearson Education Limited, Edinburgh Gate. Pp 5, 494, 685.
Aldridge, S. Recent Elucidation of Role in a Myriad of Diseases Has Ignited Interest in Field. Available: http://www.genengnews.com/gen-articles/epigenetics-offers-strategies-for-new-drugs/3168/. Date accessed: 10-08-2010.
Sardi, B. (2010). Commonly Used Drugs Can Wreck Your Genes. Available: http://www.antiagingdoctor.co.za/?p=225. Date accessed: 10-08-2010.
Merck Sharp & Dohme Corp. (2010). Cutaneous T-cell Lymphoma (CTCL) Treatment and Information. Available: http://www.zolinza.com/vorinostat/zolinza/consumer/cutaneous-t-cell-lymphoma-treatment.jsp. Date accessed: 15-08-2010.
Anon. (2006). Glossary of oncology 2006. Availabla: http://cueflash.com/decks/Oncology_2006. Date accessed: 15-08-2010.
Healthcare Professionals VIDAZA.com. (2006). VIDAZA. Available: http://vidaza.com/hcp/default.aspx. Date accessed: 15-08-2010.
NIH/National Institute of Environmental Health Sciences. (2009). NIH to fund grants for epigenetic research.Available:http://www.news-medical.net/news/20090917/NIH-to-fund-grants-for-epigenetic-research.aspx. Date accessed: 15-08-2010.
