Why do we respond so differently to drugs?
When we have a headache, one of the drugs we might take is called codeine. Codeine is converted into morphine by enzymes in the liver, and it is the morphine that actually provides pain relief (by binding to particular chemical receptors in the brain).
But several different forms of the liver enzyme exist, and these forms all differ from one another in their ability to metabolise codeine. People with a low-activity enzyme may not make enough morphine for effective pain reflief, while others with a high-activity enzyme may end up with such high levels of morphine in their system that it becomes toxic.
These differences arise because of variation in the gene encoding the liver enzyme. About 1 in 10 Caucasians are poor at converting codeine into morphine because they have a 'weak' gene. On the other hand a small percentage of people have multiple copies of the gene, and are 'supermetabolisers' - they convert codeine to morphine so well that they are at risk of morphine poisoning.
Pharmacogenetics may look for signature genetic factors linked to drug effects, but it is differences in the function of the proteins that these genes code for which are actually responsible for the differing responses to drugs.
Sites of action
There are two main ways in which a pharmacogenetic effect may occur:
- through the action of enzymes, particularly in the liver, that metabolise drugs, as in the case of codeine;
- through variation in the molecule that a drug binds to (its target).
The key liver enzymes involved in our response to drugs are cytochrome P450 (CYP) enzymes, whose main job is to deal with toxins we ingest. There are many different CYP enzymes, and each one comes in different forms, so there is a great deal of variation in the CYP system.
Drug targets tend not to be so variable, but some proteins do come in different forms that interact with a drug in different ways. This is one reason why some people are particularly sensitive to the blood-thinning agent warfarin.
