CYP2D6 is the rather cryptic name for one of a handful of very important liver enzymes, the cytochrome P450 enzymes. Cytochrome P450 (CYP) enzymes are largely responsible for detoxifying substances that are foreign to the body. The 2D6 form of cytochrome P450 is particularly important, since in detoxifies roughly 25% of the drugs used today. Individual differences in the structure of CYP2D6 can have profound effects of the concentration and activity of drugs and vitamins.
How CYP2D6 Works
CYP2D6 is a mixed-function enzyme that breaks down
xenobiotics (molecules not normally produced by the body). CYP2D6 metabolizes (breaks down) many different xenobiotics including various antidepressants, antipsychotics, antiarrhythmics, analgesics, and beta-blockers. One of the main ways that CYP2D6 metabolizes molecules is to remove a methyl group from the drug, usually rendering it inert. In this state, the drug is usually more easily removed from the body.
A few drugs are actually activated by CYP2D6. When CYP2D6 removes a methyl group from codeine, for example, it turns codeine into codeine-6-glucuronide and morphine, a powerful analgesic. In fact, the codeine that is swallowed is a pro-drug, and has virtually no pain-killing properties until it is activated by the liver enzyme, CYP2D6.
The Many Variations of CYP2D6
The CYP2D6 enzyme is a large protein; its structured is determined by the CYP2D6 gene. Quite impressively, there are over 90 known genetic variations in the CYP2D6 gene, leading to different forms of CYP2D6 enzymes. This genetic variation and differences in the enzyme structure of CYP2D6 have profound clinical implications.
Variations in CYP2D6 Determines Drug Metabolism
The structure of CYP2D6 determines the speed at which drugs are metabolized, or if they are metabolized by CYP2D6 at all. The variants of CYP2D6 can be grouped into four functional categories:
Poor metabolizers – virtually no CYP2D6 activity
Intermediate metabolizers – markedly reduced CYP2D6 activity
Normal (extensive) metabolizers – most people fall into this category
Ultrarapid metabolizers – Describes a fraction of people that have much greater than normal CYP2D6 activity
Why Variations in CYP2D6 are Clinically Important
The clinical importance of these distinctions can be illustrated with two drugs, codeine and paroxetine (Paxil), an SSRI antidepressant. If you gave a CYP2D6 poor metabolizer codeine, it would have no effect, because the drug would not be activated. Conversely, if you gave a CYP2D6 poor metabolizer paroxetine, the person would have very high levels of drug in the blood, because the liver would not metabolize and detoxify it.
The opposite is true for a CYP2D6 ultrarapid metabolizer. A normal codeine in these individuals would cause a higher than expected level of morphine, a high rate of activation. On the other hand, paroxetine would be metabolized so quickly that it would not achieve levels in the body needed to act as an antidepressant.
Most people are “normal” metabolizers, so most drugs are metabolized and detoxified at an expected rate. However, CYP2D6 ultrarapid metabolizers may be unaffected by 25% of drugs on the market because they break the drugs down too quickly. CYP2D6 poor metabolizers conceivably have a worse fate. Roughly 25% of drugs on the market will reach toxic levels in the body because CYP2D6 poor metabolizers simply cannot break them down.
What You Can Do
If you have ever had a “strong reaction” to a drug or a drug “had no effect” on you, you may be a poor or ultrarapid metabolizer. Fortunately, genetic tests are now available to detect CYP2D6 variants. These results could be provide critical information for your doctor before prescribing medications.