CYP2D6: Variants that cause reactions to common medications

Say you aren’t feeling well, have had a cold for a week, and can’t sleep…  You’re just plain miserable.  And 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 not react the same way to dextromethorphan! I know several people who have bad reactions to cough medicine, waking 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 which causes 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)
  • hydrocodone
  • methadone
  • 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

The CYP2D6 enzyme also metabolizes substances that your body produces naturally, including:[ref][ref]

  • serotonin
  • pregnenolone
  • cholesterol
  • androsterone
  • eicosanoid

 

Speeding up and slowing down

There are several important variants in the CYP2D6 gene which can cause the enzyme to function differently — either speeding up or slowing down the rate at which medications are broken 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 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.


CYP2D6 Genetic Variants

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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 -/- : CYP2A6*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 .

There are other (rare) variants for CYP2D6 not covered by 23andMe or AncestryDNA. Thus, the above list does not cover all gene variants.


Lifehacks:

The main take-away 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.

There are also substances that inhibit the CYP2D6 enzyme.

CYP2D6 Inhibitor + CYP2D6 genetic variant = problems (maybe)

Common CYP2D6 inhibitors include:

  • CBD oil [ref]
  • Nicotinamide, niacin (vitamin B3) [ref]
  • Cimetidine (Tagamet) [ref]
  • Celecoxib (Celebrex) [ref]
  • Cocaine (just don’t do cocaine…)

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.

Originally published 6/2015. Revised on 4/26/19.



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.