CYP2D6 Gene - An Introduction
The CYP2D6 gene or the cytochrome P450 2D6 contains instructions for the production of the CYP2D6 enzyme. The enzyme production predominantly occurs in the liver. CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs.
Drug metabolism is the process by which the body breaks down pharmaceutical drugs and other chemicals from the system using enzymatic systems. Drug metabolism can make the drug more active, inactive, or convert it into a more toxic metabolite (intermediary substance).
CYP2D6 belongs to the group of enzymes that are responsible for activating and metabolizing certain drugs. In some cases, the enzyme converts the inactive drug (called the prodrug) into its active form. Most ACE inhibitor drugs used to treat hypertension are prodrugs.
Amitriptyline, an antidepressant drug, on the other hand, is broken down and inactivated by the CYP2D6 in the liver.
CYP2D6 - The Different Metabolizer Types
Considerable differences exist in the efficiency and amount of CYP2D6 enzyme produced across individuals. Depending on this, they are categorized into one of the four metabolizer statuses:
Poor metabolizers (PM) - These are people who produce no or very little of the CYP2D6 enzyme. These individuals cannot process certain medicines well, and in some cases, drugs remain in the body for a longer time without getting cleared out. This increases the toxicity of the drug.
Intermediate metabolizers (IM) - These people can produce and process moderate amounts of the CYP2D6 enzyme. About 3 in 10 people are intermediate metabolizers.
Normal/extensive metabolizers (EM) - About 6 in 10 people are normal metabolizers. Their bodies produce normal levels of the CYP2D6 enzyme and activate and clear drugs at a normal rate.
Ultra-rapid metabolizers (UM) - These people have excess CYP2D6 enzyme activity. Drugs are metabolized very quickly and cleared from the body rapidly. This reduces the effectiveness of the drugs.
Drugs That The CYP2D6 Gene Act On
Codeine - Codeine is an opioid pain reliever commonly prescribed to treat chronic cough, pain, and diarrhea. It needs to be activated to morphine by the CYP2D6 enzyme for it to function efficiently.
PM have low CYP2D6 enzyme levels and may not convert codeine to morphine effectively. As a result, they may not experience the pain-relieving effect of morphine at normal codeine doses.
Tramadol - Tramadol is also an opioid pain reliever used to treat moderate to moderately severe pain. It is converted into O-desmethyltramadol (M1) in the liver, which produces the opioid pain-relieving effect. This conversion is facilitated by the CYP2D6 enzyme.
Amitriptyline - Amitriptyline helps treat anxiety and depression by preventing serotonin reuptake and thereby boosting serotonin levels in the body. CYP2D6 is involved in the metabolism of amitriptyline.
The FDA-approved drug label for amitriptyline states that CYP2D6 PM have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. In such cases, a lower starting dose or an alternative drug is recommended.
Metoprolol and propranolol - Both metoprolol and propranolol are beta-blockers. These are used in the treatment of heart diseases and hypertension.
They are primarily metabolized by CYP2D6. PM who lack CYP2D6 activity tend to have almost 5-fold higher levels of metoprolol and may be at an increased risk of side effects if administered the normal start dose.
Fluoxetine, Paroxetine - Both Fluoxetine and Paroxetine are Selective Serotonin Reuptake Inhibitors (SSRI) and are popular antidepressants.
The CYP2D6 enzyme helps convert the drugs into their active forms.
In PM, the drugs remain in the system for a longer time, risking overexposure. A lower starting dosage is recommended for such individuals.
Natural hormones and lipid - The CYP2D6 enzyme also metabolizes few naturally occurring substances in the body, including:
- Serotonin
- Androsterone
- Pregnenolone
- Cholesterol
CYP2D6 Inducers and Inhibitors
Inducers are substances that increase the metabolic activity of the enzyme. Inhibitors are substances that bind to the enzyme to reduce its activity.
Drugs that Induce CYP2D6 Activity
- Dexamethasone - used to relieve inflammation and treat rheumatic problems, skin diseases, severe allergies, and asthma
- Rifampin - an antibiotic used to treat bacterial infections
Inducers speed up the metabolism of the drugs, resulting in lower concentrations for drugs that are metabolized to an inactive form. In the case of antibiotics, inducers make the enzymes quickly convert them into their inactive forms, not giving the drugs enough time to fight the bacterial infections.
Drugs that Inhibit CYP2D6 Activity
Many drugs inhibit the activity of the CYP2D6 enzyme. Some of them include:
- Quinidine - used in the treatment of atrial and ventricular arrhythmias
- Paroxetine - used to treat major depressive disorder, panic disorder, OCD, social phobia, and generalized anxiety disorder
- Amiodarone (Cordarone) - used to treat and prevent a number of types of irregular heartbeats
- Bupropion (Wellbutrin) - used to treat depression
- Diphenhydramine (Benadryl) - an antihistamine mainly used to treat allergies
- Fluoxetine (Prozac) - used as an antidepressant
- Paroxetine (Paxil) - used as an antidepressant
- Terbinafine (Lamisil) - used as an antifungal medication.
Estimates suggest that up to nearly a third of patients on tamoxifen are also taking antidepressants. Tamoxifen is a drug used to prevent breast cancer in women and treat breast cancer in women and men. Antidepressants like Fluoxetine (Prozac) and Paroxetine (Paxil) can substantially inhibit CYP2D6 and may reduce tamoxifen efficacy.
Variations in the CYP2D6 gene
The CYP2D6 gene has a lot of variations (changes) that affect the efficiency of the CYP2D6 enzyme.
| Haplotype | Effect |
| CYP2D6*3 | Inactive enzyme |
| CYP2D6*4 | Inactive enzyme |
| CYP2D6*6 | Inactive enzyme |
| CYP2D6*7 | Inactive enzyme |
| CYP2D6*8 | Inactive enzyme |
| CYP2D6*9 | Decreased enzyme activity |
| CYP2D6*11 | Inactive enzyme |
| CYP2D6*12 | Inactive enzyme |
| CYP2D6*14 | Inactive enzyme |
| CYP2D6*41 | Decreased enzyme activity |
A haplotype is a group of gene changes that are inherited together. The *3, *4, *14, *41, etc., are star alleles. Star alleles are used to name different haplotypes.
The *4 allele is one of the most common mutations in Caucasians, resulting in a decrease in or complete lack of CYP2D6 enzyme activity. This allele accounts for 70% of all inactivating alleles that Caucasians are born with.
Recommendations To Boost CYP2D6 Metabolism
Foods that Induce CYP Enzyme Activity
- Rosemary
- Fish oil
- Chicory root
- Rooibos tea
- Garlic
- Cruciferous vegetables
- Curcumin
- Green tea
Vitamins and Minerals That Support CYP Enzyme Activity
- Vitamin B12
- Folate
- Riboflavin (vitamin B2)
- Niacin (vitamin B3)
- Pyridoxine (vitamin B6)
- Flavonoids
- Branched-chain amino acids (leucine, isoleucine, valine)
Genetic Testing
Genetic testing will help identify the metabolizer status of an individual for a gene (or group of genes) or a drug (or group of drugs). Depending on the genetic results, doctors can then plan drug dosages and opt for safer medications.
CYP2D6 Inhibitors
Even if you are not a poor metabolizer genetically, the use of CYP2D6 inhibitors will bring down the enzyme activity. This can cause over-exposure to drugs that the CYP2D6 enzyme acts on.
CYP2D6 Poor Metabolizers
For CYP2D6 poor metabolizers, CPIC recommends using an alternative hormonal therapy instead of tamoxifen for postmenopausal women.
Summary
- The CYP2D6 gene helps produce the CYP2D6 enzyme. This enzyme is responsible for clearing 25% of all clinically used drugs from the body.
- People can be grouped into 4 categories, depending on the CYP2D6 enzyme activity – Poor metabolizers, Intermediate metabolizers, Normal/extensive metabolizers, Ultra-rapid metabolizers.
- In poor metabolizers, the drug is cleared very slowly from the system, and the person is exposed to the drug for a longer time.
- Ultra-rapid metabolizers metabolize drugs very fast, and the drugs don’t have the time to work.
- The CYP2D6*4 haplotype and the CYP2D6*7 haplotype both lead to reduced enzyme activity and, as a result, increase the risk for drug overexposure.
- Genetic testing will tell what kind of a metabolizer a person is. This will be useful to plan optimal drug doses.
References:
- https://pubmed.ncbi.nlm.nih.gov/29970487/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600063/
- https://www.snpedia.com/index.php/Rs5030867
- https://pubmed.ncbi.nlm.nih.gov/27043475/
- https://en.wikipedia.org/wiki/CYP2D6
- https://pubmed.ncbi.nlm.nih.gov/9089660/
- https://www.geneticlifehacks.com/liver-detox-genes-cyp2d6/
- https://www.pharmvar.org/htdocs/archive/cyp2d6.htm
