The Omics Blog with Dr. James Weiss – Pharmacogenomics
The next stop on our journey toward understanding the science of genomics is pharmacogenomics. Who has been to the doctor and walked out with a prescription for some medicine? Let’s explore what part our genes play in the metabolism of two drugs, 6-mercaptopurine and codeine. The story gets a little technical, so fasten your seat belt.
As I mentioned in the introductory entry of this blog series, the ‘exome’ is that portion of our chromosomes that make up our genes and represents only 1.5% of our total DNA. Genes code for proteins, which are the molecules that do the work of our body. Some proteins are called enzymes. They help facilitate the many and varied biochemical reactions that take place in our body everyday. Drugs are foreign substances in the human body and must be metabolized and detoxified. Certain enzymes are responsible for this metabolism and detoxification. Pharmacogenomics describes how our genes drive this process. We will explore the pharmacogenomics of 6-mercaptopurine, which is one of the earliest uses of pharmacogenomics in clinical practice and illustrates how many young children’s lives have been saved; and codeine, a common drug with some uncommon pharmacogenomics. You will see how, if the prescribing doctor knows their patient’s individual genetic profile before the first dose is taken, side effects and even death can be avoided.
6-mercaptopurine was first synthesized in 1951 and has been very effective in treating certain types of leukemia. For example, it is used in treating acute lymphocytic leukemia (ALL), the most common form of childhood leukemia, and one that now has a 90% cure rate. Doctors found that a small number of children, who, when treated with 6-mercaptopurine, had severe side effects, including bone marrow suppression. Many died from this toxicity. The enzyme thiopurine S-methyltransferase (TPMT) is responsible for metabolism of 6-mercatopurine. Doctors working at the Mayo Clinic discovered that the TPMT gene codes for the TPMT enzyme. Six percent of the population has the form of the TPMT gene that makes them ultra-slow metabolizers and are therefore at risk for severe toxicity when given conventional doses of the drug. When those patients whose genetics make them ultra-slow metabolizers are given a much smaller dose of the drug however they avoid the life threatening toxicity yet their cancer is still treated appropriately. The FDA now recommends that all patients who are to receive 6-mercaptopurine have their TPMT gene tested before they receive the first dose, so the proper dose may be administered for each patient.
Codeine is an example of a pro-drug meaning, in its native form, it is inactive and must be metabolized by an enzyme, in this case, into morphine, the active substance. The CYP2D6 gene codes this for the enzyme. Genes vary from person to person and approximately 10% of the population does not have a functional form of the CYP2D6 gene so they cannot covert codeine into morphine. These individuals, when given codeine, will only experience the side effects (toxicity) and have none of the anticipated analgesic (pain killing) effects. Others have more than two copies of the functional portion of their CYP2D6 gene and are therefore rapid metabolizers. These patients can convert codeine into morphine so efficiently that they might actually suffer a morphine overdose after taking oral codeine. A practitioner with prior knowledge of their patients’ CYP2D6 genetics can either avoid prescribing codeine or adjust the dose and avoid toxicity while providing the desired effect.
Imagine you are sitting with your doctor and you both agree that you need to start taking a drug that is new to you. Wouldn’t you like to know, before you take the first pill, that you are getting a drug that is both the right one for you and at the right dose? That would be the science of pharmacogenomics applied right at the point of care. While this practice has already started on a small scale, in the not too distant future this will become the standard of care and be applied every time a drug is prescribed.