P450 Enzymes and Medication Metabolism

While most people don’t need medicine regularly, the vast majority of us have benefitted from medication at some time or other. Sometimes the medicine doesn’t seem to do what we expect it to do, and that might be due to genetics affecting the way that we metabolise those medicines. Mast medications rely on particular enzymes connected to Cytochrome P450 to be metabolised. Having a variation in the genes that control the expression of these enzymes can mean that a medication that would normally address the medical issue they have been prescribed for may either not work at all, or be metabolised faster than is helpful. Fortunately, in Australia, this can be checked by your pathologist following a referral from your GP.

Most people don’t need to do this. If your specific traits fit a diagnosis and the medication prescribed for you to treat and or manage that diagnosis is working as expected, then either that medication doesn’t require these enzymes, or your enzyme expression is within the expected type and quantity to metabolise the medication. 

Picture of various medication pills
By MorgueFile : see [1], CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1570359

There are two major enzymes that I want to bring to your attention: CYP2D6 and CYP2C19. The kinds of medications that are affected by CYP2D6 include many antidepressants (SSRI, TriCyclic/ some SNRIs), neuroleptics, some antiarrhythmics, lipophilic β-adrenoceptor blockers and opioids {Molecular Genetics of CYp2D6 [Link]} {Wiki CYP2D6 [Link]}. The kinds of medications that are affected by CYP2C19 are antidepressants (as above), benzodiazepines, proton pump inhibitors and antiepileptic drugs, while the CYP2C19 enzyme also affects the metabolism and management of cholesterol, steroids (including sex hormones) and other lipids {Wiki CYP2C19 [Link]}.

Two important caveats before you rush out to get that gene test.

Firstly, some medications and foods can hinder CYP2D6 and CYP2C19, effectively reducing the metabolism of the medication that need these enzymes. Generally your medical professional should know that these two medicines shouldn’t be prescribed at the same time (without the intention to have one slow down the metabolism of the other) {Clinical Pharmacogenetics Implementation Consortium Guideline [Link]}, or to warn you not to consume a food that can adversely affect metabolism. Sometimes health professionals don’t know all of the medications you are taking (scripted, “alternative medicine” or not scripted), didn’t do their due diligence and check to ensure that the combined medications were not adversely affecting each other (contraindication means something else), or forgot to warn you about inhibitory foods. Substances to be mindful of include strong citrus, cannabis, St John’s Wort, ginseng and milk thistle as these can all inhibit these enzymes {Food, drink and substances affecting CYP450 [Link]}.

Secondly, for a medication to work, the diagnosis has to be correct (I’m simplifying here). Prescribing an SSRI (Select Serotonin Reuptake Inhibitor) for the depression symptom caused by certain serotonin problems can be highly effective, but not terribly helpful for people who experience depression due to unmedicated ADHD {ADHD Primer [Link]}, financial hardship or low iron. Sometimes we need to look at the root cause for the symptom we are experiencing rather than assuming there is a gene driven enzyme variance.

While I have highlighted CYP2D6 and CYP2C19 in particular as they most affect the people that see me for therapy, it is important to be aware that there are 4 other P450 enzymes that may be relevant to you: CYP1A2, CYP 2C9, CYP2E1 and CYP3AF. While all of these can be found in the liver as part of the metabolic process, CYP3A4, CYP2D6 and CYP3A4 can be found your gut wall (intestinal tract) {Role of cytochrome P450 in drug interactions [Link]}.

We evolved these enzymes to assist catalyse various important body chemistry processes. I couldn’t find any specific symptoms of gene variation on their own, just literature regarding how this affects the metabolism of medication. Modern medications have mostly unwittingly capitalised on these enzymes to metabolise medicines mostly via your liver, and in some cases in your brain {Meta-analysis Probability Estimates Worldwide Variation [Link]}.

Both the CYP2D6 and CYP2C19 enzymes are part of the cytochrome P450 system. The genes that control your expression of these enzymes can be variant in two major ways. You can have gene deletion, where you don’t have the gene to create that enzyme in the first place, or you can have polymorphism, where you have multiple copies of the gene. Polymorphism can lead to variant versions of the enzyme, some of which can significantly impact your medication metabolism {Genetic polymorphism of CYP2C19 [Link]}. Generally, most populations have between 2 to 6% chance of variance in these genes, however it must be noted that some ethnic genotypes have higher likelihood of having variations in specific directions (deletion or polymorphism) {Cyp2D6 Overview: Allele and Phenotype Frequencies [Link]} {Meta-analysis Probability estimates worldwide variation [Link]}. Separately to that, Neurodivergent people have a moderately higher statistical likelihood than their ethnic genotype of having variation in these genes {CYP450 2D6 and 2C19 genotypes in ADHD [Link]}.

If you have found that a range of the medication types discussed here are not very effective, it is a good idea to talk to your GP or Psychiatrist about the reasonable possibility that you have a P450 CYP2D6 / CYP2C19 gene anomaly and discuss whether getting a pathological gene screen for this is suitable {GP Australia, Pharmacogenomics in general practice: The time has come [Link]}. With the confirmation that your genetic expression of these enzymes is varied, your prescribing professional can factor how that can affect potential medications. Conversely, knowing that this is not affecting you can allow further investigations into whether some other factor is interfering with your medication or whether your diagnosis needs to be re-explored.

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