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  Personalized Medicine

By Amy Adams, MS

Reviewed by John Shon, MD



Doctors have long known that people have very different reactions to drugs such as pain-killers, antidepressants, and many blood pressure and asthma medicines. It turns out that these varied reactions stem from small changes in our DNA. In some cases, these changes mean that people require a slightly different dose of the medication. In other cases, medications that are safe and effective for one person may be deadly for another.

As researchers learn more about human genetics, doctors will be able to prescribe medications based on each individual patient's genetics. Prescribing medication in this way is also called "pharmacogenomics."

 
 
 

Drug Processing in the Body

Some drugs require processing by the body before they become effective.
When you take a drug, it often requires some processing by proteins in the body in order to do its job. Some proteins in the liver switch the drug from an inactive to an active form. Other proteins help clear the drug from the body. One example of a drug that requires processing by proteins in order to do its job is codeine, which only becomes active when it is modified by proteins in the liver.

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How Do Genes Affect Our Reaction to Drugs?

Mutations in certain genes can impact how you process drugs.
Because the instructions for making each of our proteins is typically contained in a single gene, small genetic changes can impact the form and function of that protein. In the case of proteins that process drugs, an altered gene may make a protein that fails to activate a given drug, or activates it inefficiently so that only some of the drug has any affect on the body. Changes in other proteins may cause the body to eliminate or deactivate a drug before the drug has had an effect, or to fail to eliminate the drug so it lingers in the bloodstream causing unwanted side effects. Each of these protein alterations changes how a person reacts to a drug, and explains why you may react differently to a medication than another person.

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The Future of Drug Prescriptions

In the future, a person's genetic profile may be available in their medical records, giving doctors an at-a-glance guide to what drugs will be effective for that person.
If doctors knew how each person's body handled different drugs, they could prescribe the right amount of the right drug rather than having to guess as they do today. For example, if your doctor knows that you do not process codeine properly, they could prescribe a different pain medication that would be effective for you. In fact, in the future a person's genetic profile may be available in their medical records, giving doctors an at-a-glance guide to what drugs will be effective for that person.

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Current Examples of Drug Reactions

Two well studied examples of genes that affect how different people process drugs are N-acetyltransferase and P450.

N-Acetyltransferase
In the1940s doctors noticed that some people developed serious side effects from an antituberculosis drug. Much later, doctors realized that these people had a mutation in a gene called N-acetyltransferase (NAT), which adds a small molecule to drugs as they pass through the liver or intestine. This small molecule helps some drugs become effective, detoxifies some cancer-causing substances – such as those found in tobacco smoke – or causes substances found in some cooked meats to become more carcinogenic.

It turns out that there are four different forms of NAT. One form – called the fast form – causes people to process drugs very efficiently, and therefore to respond well to those drug. The three other forms of the gene cause a person to process drugs very slowly. People who have these three forms of the gene, referred to as slow acetylators, respond poorly to some drugs and tend to show more side-effects because the unprocessed chemical remains at high levels in the blood. It was these slow acetylators who had responded poorly to the antituberculosis drug.

Because N-acetyltransferase is also involved in processing cancer-causing chemicals, fast and slow acetylators have different risk levels for some cancers; fast acetylators are at high risk for colon cancer, while slow acetylators are at increased risk for bladder cancer. Post-menopausal women who are slow acetylators are also more likely to develop breast cancer as a result of smoking, according to one study.

All three slow forms of NAT are autosomal recessive. That is, a person has to inherit a slow form of the gene from both parents in order to be a slow acetylator. About 50 percent of people of Caucasian descent are slow acetylators.

Although being a fast or slow acetylator is a genetic change, researchers determine a person’s acetylation status through a urine test rather than through DNA testing. The person drinks a small amount of caffeine, which is processed by N-acetyltransferase. After five or six hours, the doctor looks for certain chemicals in the urine that indicate that the caffeine has been processed. If only a small percentage has been processed, then the person is considered a slow acetylator. This test, and other tests that measure how a person processes drugs, are not commonly used at this time, although experts suggest that they may become more common in the future.

P450
A group of genes called P450s play an important role in how drugs and toxins are processed in the liver. There are several different P450 genes, each of which makes a protein that modifies a different subset of drugs. One particular P450, named CYP2D6, comes in two forms. Seven to ten percent of Caucasians have a form of CYP2D6 that does not effectively process some drugs, including codeine and some antidepressants, antipsychotics, and heart disease medications. DNA tests are available to determine which variation of CYP2D6 a person has, and therefore what drug – and what drug doses – may be most effective for that person. Again, doctors rarely give patients a genetic test for CYP2D6 before prescribing a medication. Instead, they simply try a different medication if the first one isn’t effective in a patient.

Drugs Processed by CYP2D6

  • Amphetamine
  • Codeine
  • Tamoxifen
  • Carvedilol
  • Timolol
  • Amitriptyline
  • Imipramine
  • Haloperidol
  • Lidocaine
  • Ondansetron

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References

Adapted from the National Institute of General Medical Sciences "Medicines for You" http://www.nigms.nih.gov/funding/medforyou.html (downloaded October 25, 2000)

Evans DAP, Manley KA, McKusick VA. (1960). Genetic control of isoniazid metabolism in man. Br Med J. 2:485-490

Laviero M., Cronin, M., Sadee, W. (2000) Pharmacogenomics: The Promise of Personalized Medicine. AAPS Pharmsci. 2(1):article 4.

Hughes HB, Biehl JP, Jones AP, Schmidt, LH. (1954) Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis. Am Rev Tuberculosis.70:266-273.

Daniels, L., Blankson, E.A., Henderson, C.J., Harris, A.H., Wolf, C.R., Lennard, M.S., and Tucker, G.T. (1992). Delineation of human cytochromes P450 involved in the metabolism of tamoxifen. Br J Clin Pharmacol. 33:153P

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