rs5030655 — CYP2D6 *6

CYP2D6*6 — A Critical No-Function Allele for Drug Metabolism

CYP2D6*6 is one of the most clinically important no-function alleles of the highly polymorphic CYP2D6 gene.

This variant is characterized by a single-nucleotide deletion in exon 3 (c.454del, legacy name 1707delT) causing a frameshift and premature truncation of the CYP2D6 protein , resulting in complete loss of enzyme function. The CYP2D6 enzyme is responsible for metabolizing approximately 20-25% of all prescription drugs, including many opioids, antidepressants, and antipsychotics.

The Mechanism

The 1707delT deletion causes a frameshift from codon 118 leading to a truncated non-functional protein, resulting in missed enzyme activity . Without functional CYP2D6 enzyme, individuals cannot properly metabolize drugs that depend on this pathway. For prodrugs like codeine and tramadol that require CYP2D6 to convert them into active metabolites morphine and O-desmethyltramadol, respectively¹¹ morphine and O-desmethyltramadol, respectively
These conversions are essential for pain relief, the consequence is complete lack of therapeutic effect. For drugs that are inactivated by CYP2D6, such as many antidepressants, poor metabolizers experience dangerously high drug levels and increased side effects.

The Evidence

The frequencies of CYP2D6*6 are approximately 1% in European populations and 0.5% or lower in other populations . Original characterization²² Original characterization
Saxena et al. identified this single base deletion in poor metabolizers in 1994. Hum Mol Genet 1994. The variant has since been extensively studied and included in all major pharmacogenomic guidelines.

For CYP2D6 poor metabolizers (activity score of 0), current evidence supports the avoidance of codeine and tramadol due to the likelihood of suboptimal or lack of effect, while codeine or tramadol should not be used in ultrarapid metabolizers to avoid the risk of severe toxicity . CPIC Level A evidence³³ CPIC Level A evidence
Clinical Pharmacogenetics Implementation Consortium guidelines provide the strongest recommendations for avoiding these drugs in poor metabolizers. Clin Pharmacol Ther 2021.

For antidepressants, the pattern reverses.

For poor metabolizers taking venlafaxine, there are indications of an increased risk of side effects and a reduced chance of efficacy due to reduced conversion to the active metabolite O-desmethylvenlafaxine . Case report⁴⁴ Case report
A CYP2D6 poor metabolizer experienced severe adverse effects and no therapeutic benefit from venlafaxine. Ann Clin Biochem 2009.

Practical Implications

Carrying one or two copies of CYP2D6*6 has profound implications for medication selection:

Pain management: Avoid codeine and tramadol entirely. These prodrugs require CYP2D6 for activation. Alternative opioids not metabolized by CYP2D6 include morphine, oxymorphone, buprenorphine, fentanyl, methadone, and hydromorphone.

Antidepressants: For drugs heavily metabolized by CYP2D6 (paroxetine, fluvoxamine, venlafaxine, vortioxetine), poor metabolizers experience elevated drug levels and increased side effects. Alternatives include citalopram, escitalopram, sertraline, and mirtazapine, which rely more heavily on other metabolic pathways.

ADHD medication:

Atomoxetine-treated patients with an activity score of 0 are poor metabolizers who may experience higher drug levels , requiring dose reduction or alternative therapy.

Cancer treatment: Tamoxifen, used for breast cancer, requires CYP2D6 for conversion to its active form endoxifen. Poor metabolizers may have reduced benefit from tamoxifen therapy.

Interactions

CYP2D6*6 interacts with other CYP2D6 alleles to determine overall metabolizer status. Two no-function alleles (such as *6/*6, *6/*4, or *6/*3) result in poor metabolizer status. One no-function allele paired with one reduced-function allele (such as *6/*10 or *6/*41) results in intermediate metabolizer status. These compound genotypes may warrant different dosing recommendations depending on the specific drug. Additionally, strong CYP2D6 inhibitors (such as fluoxetine, paroxetine, and bupropion) can convert normal metabolizers into phenotypic poor metabolizers, further complicating drug therapy.