CYP2D6 *4 (rs3892097): Drug Metabolism

CYP2D6 metabolizes approximately 25% of all prescription drugs, making it one of the most important drug-metabolizing enzymes. The *4 allele is the most common non-functional variant in Europeans, causing a complete loss of enzyme activity from that allele. This affects how you respond to codeine, tamoxifen, many antidepressants, antipsychotics, and numerous other medications.

Understanding CYP2D6

CYP2D6 is highly polymorphic with over 100 known variants:

• Substrates: ~25% of prescription drugs
• Key drug classes: Opioids, antidepressants, antipsychotics, beta-blockers, tamoxifen
• Phenotypes: Poor, intermediate, normal, and ultrarapid metabolizers
• Clinical impact: Among the most actionable pharmacogenes

The *4 Allele

*4 is a null allele - it produces no functional enzyme:

• G allele (*1): Normal function
• A allele (*4): Splicing defect - no functional enzyme produced

Understanding Your Genotype

• *1/*1: Normal metabolizer (100% activity)
• *1/*4: Intermediate metabolizer (~50% activity)
• *4/*4: Poor metabolizer (no CYP2D6 activity)

Activity Score System

CYP2D6 uses an activity score for phenotype prediction:

• *1 = 1 point (normal function)
• *4 = 0 points (no function)
• Total score determines metabolizer status

Codeine and Opioid Prodrugs

How Codeine Works

• Codeine is a prodrug - must be converted to morphine for effect
• CYP2D6 performs this conversion
• *4/*4 (poor metabolizers) get minimal pain relief from codeine
• ~10% of Europeans are poor metabolizers

Clinical Implications

Other Affected Opioids

• Tramadol: Also requires CYP2D6 activation
• Hydrocodone: Partially CYP2D6 dependent
• Oxycodone: Minor CYP2D6 involvement

Tamoxifen and Breast Cancer

Activation Required

• Tamoxifen requires CYP2D6 conversion to endoxifen (active metabolite)
• Poor metabolizers have lower endoxifen levels
• May have reduced tamoxifen efficacy
• Critical for breast cancer treatment decisions

Clinical Guidance

• CPIC guidelines recommend avoiding tamoxifen in poor metabolizers
• Consider aromatase inhibitor alternative (postmenopausal)
• Higher-dose tamoxifen studied but not standard
• Discuss options with oncologist

Antidepressants

SSRIs and SNRIs

• Paroxetine: CYP2D6 substrate - poor metabolizers have higher levels
• Fluoxetine: Substrate and inhibitor of CYP2D6
• Venlafaxine: Converted to active metabolite by CYP2D6
• Poor metabolizers: May need dose reductions or alternatives

Tricyclic Antidepressants

• Amitriptyline, nortriptyline, imipramine affected
• Poor metabolizers at increased side effect risk
• Consider therapeutic drug monitoring

Antipsychotics

Affected Medications

• Risperidone: CYP2D6 substrate - dose adjust for poor metabolizers
• Aripiprazole: Partially CYP2D6 dependent
• Haloperidol: CYP2D6 involvement

Clinical Considerations

• Poor metabolizers may experience more side effects
• Consider lower starting doses
• Monitor for extrapyramidal symptoms

Beta-Blockers

CYP2D6-Dependent Beta-Blockers

• Metoprolol: Extensively metabolized by CYP2D6
• Carvedilol: Partially CYP2D6 dependent
• Poor metabolizers: Higher drug levels, more pronounced effects

Alternatives

• Atenolol, bisoprolol less affected by CYP2D6
• Consider for patients known to be poor metabolizers

Drug-Drug Interactions

CYP2D6 Inhibitors

These drugs can convert anyone to a phenotypic poor metabolizer:

• Fluoxetine: Strong inhibitor
• Paroxetine: Strong inhibitor
• Bupropion: Moderate inhibitor
• Quinidine: Potent inhibitor

Interaction Implications

• Normal metabolizer + strong inhibitor = poor metabolizer phenotype
• Can negate codeine activation
• Can reduce tamoxifen efficacy
• Important to avoid these combinations when CYP2D6 activity needed

Prevalence

• *4 allele frequency (Europeans): ~20-25%
• *4/*4 (poor metabolizers): ~5-10% of Europeans
• African ancestry: Lower *4 frequency (~2-5%)
• Asian ancestry: Very low *4 frequency (~1%)

Comprehensive CYP2D6 Testing

Why rs3892097 Alone Isn't Enough

• CYP2D6 has many variants - *4 is just one
• Full phenotype requires testing multiple alleles
• Gene deletions and duplications also affect function
• Comprehensive panels test 10+ CYP2D6 variants

Testing with NutraHacker

NutraHacker's Complete Mutation Report analyzes CYP2D6 *4 along with other key pharmacogenetic variants, helping you understand your drug metabolism profile.

Frequently Asked Questions

Why doesn't codeine work for me?

If codeine provides no pain relief, you may be a CYP2D6 poor metabolizer (like *4/*4). Codeine is a prodrug that must be converted to morphine by CYP2D6. Without functional CYP2D6, this conversion doesn't happen, and codeine remains inactive. Alternative pain medications that don't require CYP2D6 activation, like morphine itself or non-opioid analgesics, would work for you.

I have one copy of *4 - what does this mean?

Having one *4 allele (*1/*4) makes you an intermediate metabolizer with about 50% normal CYP2D6 activity. You may have somewhat reduced response to prodrugs like codeine and tramadol, and may need dose adjustments for some CYP2D6 substrates. Effects are less dramatic than for poor metabolizers but still clinically relevant.

Should I be tested before any surgery?

Knowing your CYP2D6 status before surgery is valuable because many post-operative pain medications are CYP2D6 substrates. If you're a poor metabolizer, your anesthesiologist can plan alternative pain management. Consider preemptive testing so results are available when needed.

References

1. Crews KR, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. 2014;95(4):376-382.
2. Goetz MP, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy. Clin Pharmacol Ther. 2018;103(5):770-777.
3. Gaedigk A, et al. The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database. Clin Pharmacol Ther. 2018;103(3):399-401.