CYP2D6 gene and medication reactions

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 may wake up the next morning feeling like they were hit by a truck.

This example is just one of many medications metabolized by the CYP2D6 enzyme. Many genetic variants impact the function of CYP2D6, causing a wide variety of reactions to some commonly used medications.

CYP2D6: Breaking down medications

Medications: The CYP2D6 enzyme metabolizes (breaks down) about 25% of pharmaceutical drugs, including SSRIs, opioids, tamoxifen, dextromethorphan, and beta-blockers.

Which drugs are metabolized by CYP2D6?

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

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

  • serotonin
  • tyrosine into dopamine[ref]
  • pregnenolone
  • cholesterol
  • androsterone
  • eicosanoid

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. It can mean that the drug has less of an effect than expected.

Be aware, though, that for some medications, it is the metabolite (or what the drug is converted into) 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. It 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 cancers such as bladder or lung cancer. 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 proper dosage of certain medications. But you also need to understand how the drug works in the body:

  • Some drugs, such as tamoxifen, need to be metabolized to their active form by CYP2D6 to work.
  • Other drugs are turned into their inactive form by CYP2D6.

Remember that many drugs, toxins, and endogenous substances can be metabolized using multiple CYP enzymes. Thus, many drugs metabolized by CYP2D6 may also be broken down with other enzymes.

What does CYP2D6 do in the body?

We don’t have specific drug-metabolizing genes — just waiting around for medications to be invented :-)

Instead, the CYP enzyme is produced by cells to break down molecules produced by the body (endogenous substances).

CYP2D6 is involved in[ref][ref]

  • The metabolism of tyrosine to dopamine.
  • The turnover rate of serotonin.
  • The metabolism of anandamide, which binds to the cannabinoid receptor.

Anxiety traits:

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]

While the information on possible links to personality traits is interesting, the research also points out that medications that utilize CYP2D6 may also (somewhat) affect your mood.


CYP2D6 Genotype Report:

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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 .

 


Lifehacks:

The main takeaway 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.

  • It 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 people need to know that their genetic variants impact drug metabolism rates.

There is clinical genetic testing available through your doctor for checking gene-drug interactions. Talk with your doctor about pharmacogenomic (PGx) testing.

The rest of this article is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.

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Chavan, Bir S., et al. “A Prospective Study to Evaluate the Effect of CYP2D6 Polymorphism on Plasma Level of Risperidone and Its Metabolite in North Indian Patients with Schizophrenia.” Indian Journal of Psychological Medicine, vol. 40, no. 4, Aug. 2018, pp. 335–42. PubMed, https://doi.org/10.4103/IJPSYM.IJPSYM_83_18.

Cheng, Jie, et al. “Potential Role of CYP2D6 in the Central Nervous System.” Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 43, no. 11, Nov. 2013, pp. 973–84. PubMed Central, https://doi.org/10.3109/00498254.2013.791410.

González, Idilio, et al. “Relation between CYP2D6 Phenotype and Genotype and Personality in Healthy Volunteers.” Pharmacogenomics, vol. 9, no. 7, July 2008, pp. 833–40. PubMed, https://doi.org/10.2217/14622416.9.7.833.

Guo, Ying, et al. “Repeated Administration of Berberine Inhibits Cytochromes P450 in Humans.” European Journal of Clinical Pharmacology, vol. 68, no. 2, Feb. 2012, pp. 213–17. PubMed, https://doi.org/10.1007/s00228-011-1108-2.

Langhammer, Astrid Jordet, and Odd Georg Nilsen. “In Vitro Inhibition of Human CYP1A2, CYP2D6, and CYP3A4 by Six Herbs Commonly Used in Pregnancy.” Phytotherapy Research: PTR, vol. 28, no. 4, Apr. 2014, pp. 603–10. PubMed, https://doi.org/10.1002/ptr.5037.

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NM_000106.5(CYP2D6):C.506-1G>A AND Not Provided – ClinVar – NCBI. https://www.ncbi.nlm.nih.gov/clinvar/RCV000342450.1/. Accessed 24 Aug. 2022.

Peñas-LLedó, Eva M., and Adrián LLerena. “CYP2D6 Variation, Behaviour and Psychopathology: Implications for Pharmacogenomics-Guided Clinical Trials.” British Journal of Clinical Pharmacology, vol. 77, no. 4, Apr. 2014, pp. 673–83. PubMed Central, https://doi.org/10.1111/bcp.12227.

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


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.