Say you aren’t feeling well, have had a cold for a week, and can’t sleep…You’re just plain miserable. In your sleep-deprived state, you decide to take some Nyquil (or another cough syrup containing dextromethorphan). Some people may get relief and finally get some sleep. Others…well, they may wake up the next morning feeling like they were hit by a truck.
This is just one example, among many, of medications that are metabolized by the CYP2D6 enzyme. There are many genetic variants that impact the function of CYP2D6 causing a wide variety of reactions to some commonly used medications.
CYP2D6: Breaking down medications
The CYP2D6 enzyme metabolizes (breaks down) about 25% of pharmaceutical drugs including SSRIs, opioids, tamoxifen, dextromethorphan, and beta-blockers.
Here is a partial list of drugs metabolized by CYP2D6:
- dextromethorphan (cough syrup)
- tamoxifen (breast cancer, estrogen blocker)
- pimozide (Tourette’s medication)
- metoprolol (beta-blocker)
- propranolol (beta-blocker)
- risperidone (schizophrenia, bipolar medication)
- full list with details at PharmGKB
Speeding up and slowing down enzyme function:
Several important variants in the CYP2D6 gene can cause the enzyme to function differently — either by speeding up or slowing down the rate by which the medications break down.
- A fast CYP2D6 enzyme function is usually called an ‘extensive metabolizer’
- Slow (or no) enzyme function is referred to as a ‘poor metabolizer’.
A fast or ultrarapid metabolizer will clear the drug from their system more rapidly. This can mean that the drug has less of an effect than expected. Be aware, though, that for some medications, it is the metabolite that gives the effect. For these types of ‘pro-drugs’, an extensive metabolizer can have a more intense effect from the drug.
Slower enzyme function, for many drugs, can mean that the medication sticks around in the body longer than normal. This may affect how much you need to take or how often to take the drug.
A variant that slows down the CYP2D6 isn’t always bad. Being a poor metabolizer may reduce the risk of some cancers such as bladder or lung. On the other hand, it also may significantly increase the risk of Parkinson’s disease for those exposed to pesticides.
Knowing whether you’re a fast or slow metabolizer may make it easier to find the right dosage of certain medications. But you also need to know how the drug works in the body:
- Some drugs, such as tamoxifen, need to be metabolized to their active form by CYP2D6 in order to work.
- Other drugs are turned into their inactive form by CYP2D6.
Keep in mind that many drugs, toxins, and endogenous substances can be metabolized using multiple different CYP enzymes. Thus, many drugs metabolized by CYP2D6 may also be broken down with other enzymes.
Endogenous substances metabolized by CYP2D6:
We don’t have specific drug-metabolizing enzymes in the body, just waiting around for us to take a medication…
Instead, the CYP enzyme are produced by cells in order to break down molecules produced by the body (endogenous substances).
- The metabolism of tyramine to dopamine.
- The turnover rate of serotonin.
- The metabolism of anandamide, which binds to the cannabinoid receptor.
With the impact on neurotransmitters, researchers subsequently discovered that CYP2D6 genetic variants are linked to personality traits. For example, several studies show that CYP2D6 poor metabolizers are more likely to score lower in socialization and higher in anxiety symptoms. [ref]
CYP2D6 Genetic Variants
There are rare variants for CYP2D6 not covered by 23andMe or AncestryDNA. Additionally, copy number variants can exist, with a small portion of the population having either zero or multiple copies of this gene. These variants are also not covered in 23andMe or Ancestry testing.[ref]
Talk to your doctor about pharmacogenetics testing for full coverage.
Check your genetic data for rs3892097 (23andMe v4; AncestryDNA):
- T/T: CYP2D6*4 – poor metabolizer[ref]
- C/T: intermediate metabolizer
- C/C: typical
Members: Your genotype for rs3892097 is —.
Check your genetic data for rs5030655 (23andMe v4, v5):
- DD or -/- : CYP2D6*6 – deletion, poor metabolizer[ref]
- DI or – /A: One copy of CYP2D6*6
- II or A/A: typical
Members: Your genotype for rs5030655 is —.
Check your genetic data for rs5030656 (23andMe v4, v5):
- II or CTT/CTT: typical
- ID or CTT / -: decreased function, one copy of CYP2D6*9
- DD or – / – : decreased function, two copies of CYP2D6*9[ref]
Members: Your genotype for rs5030656 is —.
Check your genetic data for rs1065852 (23andMe v4 only):
- A/A: decreased or non-functioning, CYP2D6*10[ref][ref]
- A/G: somewhat decreased function
- G/G: typical
Members: Your genotype for rs1065852 is —.
Check your genetic data for rs28371725 (23andMe v4, v5; AncestryDNA):
- C/C: typical
- C/T: reduced activity, CYP2D6*41
- T/T: reduced activity, CYP2D6*41[ref]
Members: Your genotype for rs28371725 is —.
Check your genetic data for rs1135824 (23andMe v4, v5):
- T/T: typical
- C/T: one copy of CYP2D6*3
- C/C: two copies of CYP2D6*3, non-functioning
Members: Your genotype for rs1135824 is —.
Check your genetic data for rs5030867 (23andMe v4, v5; AncestryDNA):
- T/T: typical
- G/T: carrier of one CYP2D6*7 allele
- G/G: carrier of two CYP2D6*7, non-functioning
Members: Your genotype for rs5030867 is —.
Check your genetic data for rs28371706 (23andMe v4; AncestryDNA)
- G/G: typical
- A/G: carrier of one decreased or non-functioning allele
- A/A: possibly decreased or non-functioning
Members: Your genotype for rs28371706 is —.
Check your genetic data for rs16947 (AncestryDNA):
- A/A: *2, reduced function[ref]
- A/G: possibly reduced function
- G/G: typical
Members: Your genotype for rs16947 is —.
The main takeaway here is that if you carry a non-functioning variant, you need to be aware that drugs metabolized through CYP2D6 may not work as well for you.
- This could mean varying the dosage or timing.
- Or you may need to discuss alternative medications with your doctor.
Talk with your doctor or pharmacist if you have questions. I don’t want to steer anyone wrong here, but I do think it is important for people to know that their genetic variants impact drug metabolism rates.
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