DNA & Drugs


By Katharine Santiago


Every individual differs in terms of their genetic make-up. This has consequences in many areas of study, but it turns out our DNA affects how we respond to drugs as well.. Over the past 50 years, the study of pharmacogenomics, which looks at how genomic information can be used to individualize drug treatments, has started to evolve and play a bigger role in how drugs are administered. Because everyone has a different genome, they will respond a little differently to the same drug . Sometimes these different reactions are harmless, but they can also be dangerous, causing toxic side effects that may be deadly (Weinshilboum & Wang, 2017).


One of the most important impacts of genetic differences on the effects of a drug are differences in metabolizing enzymes between individuals. These enzymes are responsible for breaking down a drug once it is in the body. While many enzymes are important for the efficacy and breakdown of drugs, here we will focus on one: Thiopurine S-methyltransferase (TPMT), which breaks down thiopurine drugs in the body. These drugs can be used to treat a variety of things, such as Leukemia and autoimmune disorders. Some individuals have a genetic variation that results in low activity of the TPMT enzyme, and this can lead to deadly reactions to a standard dose of thiopurines. Because there is a low therapeutic window, which is the window where the drug works effectively without becoming toxic, it is easy for a higher-than-standard dose to be dangerous. Even an individual with a fully functioning TPMT enzyme can be subject to toxic side effects, so there is a greater threat to individuals with low TPMT activity. This enzyme highlights the need for more research in the field of pharmacogenomics. (Wang, et al., 2005).


There are two different forms of the TPMT gene resulting in protein breakdown. Researchers in a 2005 study hypothesized that this causes misfolding in proteins, and this was correct. When a protein folds incorrectly, and cannot function in its intended way, the cell will often break these proteins down to eliminate them. This is what occurs in individuals with the gene for low activity TPMT enzymes, leading to dangerous responses to normal doses of thiopurine drugs. (Wang, Nguyen, & McLaughlin, 2005)


Pharmacogenomics has important impacts on the safety and efficacy of drug administration. It is a growing field of study that can change the way we look at drug design and prescription. With the information we can get from the genome, medicine can be specialized for each individual to ensure optimal effects with little to no side effects. There are other aspects of drug design and administration that can cause harmful side effects,such as metabolism of drugs and production of metabolites, as well as breakdown of the drug as it travels through the body, but this is a step in the right direction to reduce these effects. However, there are many enzymes in the body and many differences in them between individuals, so there is a lot more work to be done.








Citations:

Wang, L., Nguyen, T. V., McLaughlin, R. W., Sikkink, L. A., Ramirez-Alvarado, M., & Weinshilboum, R. M. (2005). Human thiopurine S-methyltransferase pharmacogenetics: variant allozyme misfolding and aggresome formation. Proceedings of the National Academy of Sciences, 102(26), 9394-9399.



Weinshilboum, R. M., & Wang, L. (2017, November). Pharmacogenomics: precision medicine and drug response. In Mayo Clinic Proceedings (Vol. 92, No. 11, pp. 1711-1722). Elsevier.7/

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