CYP2D6: Metabolism of many OTC and prescription medicines

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 — they wake up feeling like they were hit by a truck after taking Nyquil.

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 this gene, causing a wide variety of reactions to some commonly used medications.

The CYP2D6 enzyme metabolizes about 25% of pharmaceutical drugs such as SSRI’s, opioids, tamoxifen, dextromethorphan, and beta blockers. It also metabolizes the serotonin and neurosteroids (pregnenolone, cholesterol, androsterone, etc) that your body produces naturally.

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 metabolism is usually called an ‘extensive metabolizer’, while slow (or no) enzyme function is called ‘poor metabolizer’.

There are both good and bad potential consequences of being a poor or extensive metabolizer.  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. 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.

There is a good list of drugs (substrates) metabolized by CYP2D6 on Wikipedia. Some that you may be familiar with include codeine, oxycodone, most SSRIs, several beta blockers, and tamoxifen.


CYP2D6 Genetic Variants

Check your genetic data for rs3892097  (23andMe v4; AncestryDNA):

  • T/T: CYP2D6*4 – poor metabolizer [ref]
  • C/T:  typically intermediate metabolizer
  • C/C: normal metabolism

Check your genetic data for rs5030655 (23andMe v4, v5):

  • -/- or DD : CYP2A6*6 – deletion, poor metabolizer [ref]
  • – /A or DI: One copy of CYP2D6*6
  • A/A or II: normal

Check your genetic data for rs5030656 (23andMe v4, v5):

  • I/I or CTT/CTT: normal
  • I/D or CTT / -: decreased function, one copy of CYP2D6*9
  • D/D or – / – : decreased function, two copies of CYP2D6*9 [ref]

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: normal

Check your genetic data for rs28371725 (23andMe v4, v5; AncestryDNA):

  • C/C: normal
  • C/T: reduced activity, CYP2D6*41
  • T/T: reduced activity, CYP2D6*41[ref]

Check your genetic data for rs1135824 (23andMe v4, v5):

  • T/T: normal
  • C/T:  one copy of CYP2D6*3
  • C/C: two copies of CYP2D6*3, non-functioning

Check your genetic data for rs5030867  (23andMe v4, v5; AncestryDNA):

  • T/T: normal
  • G/T:  carrier of one CYP2D6*7 allele
  • G/G: carrier of two CYP2D6*7, non-functioning

Check your rs28371706 (23andMe v4; AncestryDNA)

  •  G/G: normal
  •  A/G:  carrier of one decreased or non-functioning allele
  •  A/A: possibly decreased or non-functioning

There are other (rare) variants for CYP2D6 as well other variants not covered by 23andMe or AncestryDNA. So the above list is not exhaustive.


Lifehacks:

The main application 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 may mean varying the dosage or timing — or it may mean talking with your doctor about alternative medications.

There are also substances that inhibit the CYP2D6 enzyme. Taking a CYP2D6 inhibitor along with having a variant that decreases the function may really cause problems when stacked with a medication metabolized by CYP2D6.

Common CYP2D6 inhibitors include:

  • CBD oil [ref]
  • Nicotinamide, niacin (vitamin B3) [ref]
  • Cimetidine (Tagamet) [ref]
  • Celecoxib (Celebrex) [ref]
  • Cocaine (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.

This is part of an ongoing series on the genes involved in detoxification.

3 Comments on “CYP2D6: Metabolism of many OTC and prescription medicines

  1. My 23andme test didn’t have many of these CYP genes
    on it, but it was done about 4 years ago.
    Can you tell me the functioning of these genes? You did
    mention the first one, but please confirm on my list.

    rsID Minor Allele Genotype Phenotype
    rs1065852 A AG +/-
    rs1135840 G GG +/+
    rs16947 A AG +/-

    Also, I have 2 other CYP genes that I am unsure of:

    rs1799853 T TT +/+
    rs1801272 A AA +/+

    I can’t be sure if these +/+ genes are all are always non-functioning
    or “bad”. It looks like a lot of non-functioning detox genes.
    Is Mercury and other metals part of this group?

    Thanks so much. Maybe next month I can donate.

    • I’m wondering if you perhaps have version 3 results from 23andMe?
      An easy place to look up rs id’s to see links to research studies is http://www.snpedia.com. rs1065852 isn’t linked to a specific CYP2D6 variant that is reduced in function, but it is considered likely to be linked to reduced function. The others that you list on CYP2D6 are ambiguous on their function.

      rs1799853 is a CYP2C9 variant. Here is my article on it: https://www.geneticlifehacks.com/liver-detox-genes-cyp2c9/
      rs1801272 is a CYP2A6 variant. Here is my article on it: https://www.geneticlifehacks.com/liver-detox-genes-cyp2a6/

      The question of whether these variants are ‘bad’ is an interesting one and depends on your perspective and your phase II detoxification. The important thing to know is that they do affect drug metabolism. An easy way to check the drugs that are metabolized through that pathway is to look at the list of ‘substrates’ on the wikipedia page for that specific gene. For example, CYP2C9 metabolizes a lot of the popular NSAIDs including ibuprofen. https://en.wikipedia.org/wiki/CYP2C9

  2. Lots of good stuff!

    CYP2D6 is highly polymorphic, with over 90 known allelic variants. About 1 in 10 Caucasians are CYP2D6 poor metabolizers. Only about half that many African-Americans are. The functional copy of CYP2D6 that is present determines the rate of metabolism of CYP2D6 substrates significantly.

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