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. 

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

1. The CYP2D6 gene helps produce the CYP2D6 enzyme. This enzyme is responsible for clearing 25% of all clinically used drugs from the body. 
2. People can be grouped into 4 categories, depending on the CYP2D6 enzyme activity – Poor metabolizers, Intermediate metabolizers, Normal/extensive metabolizers, Ultra-rapid metabolizers. 
3. In poor metabolizers, the drug is cleared very slowly from the system, and the person is exposed to the drug for a longer time. 
4. Ultra-rapid metabolizers metabolize drugs very fast, and the drugs don’t have the time to work. 
5. 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.
6. Genetic testing will tell what kind of a metabolizer a person is. This will be useful to plan optimal drug doses.

References:

1. https://pubmed.ncbi.nlm.nih.gov/29970487/
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600063/
3. https://www.snpedia.com/index.php/Rs5030867
4. https://pubmed.ncbi.nlm.nih.gov/27043475/
5. https://en.wikipedia.org/wiki/CYP2D6 
6. https://pubmed.ncbi.nlm.nih.gov/9089660/ 
7. https://www.geneticlifehacks.com/liver-detox-genes-cyp2d6/
8. https://www.pharmvar.org/htdocs/archive/cyp2d6.htm

How Do Pesticides Enter The Body?

Pesticides are routinely used in agrochemical industries to prevent, repel, mitigate or kill pests that can damage the produce. It is a broad term and usually includes fungicides, herbicides, acaricides, bactericides, nematicides, rodenticides, etc. 

Based on their chemical structure, pesticides can be of the following types – Organochlorine, Organophosphorus, Carbamates, and Pyrethroids. Unfortunately, while consuming fruits, vegetables, and other products, we inadvertently consume some pesticides. 

Pesticides are called xenobiotics, i.e., foreign compounds that are not produced by the body but found in it. The organochlorine group of pesticides are the most widely used and are predominant pesticides in the environment. They also have the potential to accumulate in the body’s adipose (or fat) tissues. These pesticides alter enzyme activities and cause harmful effects on the nervous system.

Since pesticides have a long half-life (they take a long time to reduce to half of their concentration in the body), the body has to eliminate them regularly. 

Pesticides In Food

The metabolism of pesticides occurs in two phases – Phase I and Phase II reactions. Metabolism is the process by which chemicals like pesticides that enter our body are broken down into smaller components, made less toxic, and more water soluble to enable their easy elimination from the body.

In some cases, detoxification can result in the formation of a toxic product. This is called the bioactivation of a pesticide.

Pesticides are lipophilic (or fat-soluble) substances. This nature helps them to enter the cell membrane and bind to various lipoproteins in the blood. Since they are fat-soluble, they are insoluble in water and are not easily eliminated from the body. To remove them, they are converted into polar compounds that are easily eliminated from the body.

Phase I: In the first phase, these fat-soluble pesticide molecules are converted into polar compounds by adding a polar group. This process occurs either by oxidation, reduction, or hydrolysis reaction. The end product of the phase I reaction now serves as a substrate (or starting compound) for phase II reaction.

Phase II: In Phase II of pesticide metabolism, the polar compound gets attached to substances in the body such as sugars, amino acids, glutathione, phosphates, and sulfates. This conversion to a polar compound makes pesticides less toxic and easy to eliminate.

Where Does Pesticide Metabolism Take Place?

Metabolism of xenobiotics like pesticides occurs in all tissues and organs as it is a defense mechanism to eliminate toxic products and reduce any harmful effects on the organism. Though all organs and tissues show some amount of pesticide metabolism, detoxification occurs more actively in organs like the kidney, liver, and intestine. 

Enzyme groups like the Cytochrome P450 (or the CYP enzymes), NADPH Cytochrome C Reductase, and Flavin-Containing Monooxygenase (FMO) play an important role in the metabolism of pesticides in the body. Other enzymes that play a role in pesticide detoxification include dehydrogenases, reductases, and Glutathione S Transferase.

 What is Pesticide Toxicity?

Failure to eliminate pesticides from the body can lead to their accumulation and subsequent toxicity. The toxicity of pesticides is expressed in terms of LD50. It is defined as the single exposure dose of a substance per unit bodyweight of the organism and is the abbreviation for Lethal Dose 50%.

Based on this LD₅₀ value, pesticides can be of the following types, based on their toxicity scale:

Organophosphorus pesticides hinder the activity of an enzyme (acetylcholinesterase enzymes) important for the proper functioning of the nervous system. The toxicity effects of organophosphorus compounds are rapid, and symptoms appear immediately after exposure. Exposure to these pesticides can be hazardous for people with reduced lung function and a history of convulsive disorders.

Genetics Of Pesticide Detoxification/Metabolism

Two primary groups of genes are involved in the metabolism of pesticides, particularly organophosphates. These include the CYP genes and PON gene family.

Variations in the CYP Genes

CYP Genes

The CYP genes and enzymes perform a vital role in the metabolism of pesticides. Some genes that play a role include CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. In addition, CYP2B6 and CYP2C19 play an essential role in phase I detoxification of pesticide metabolism.

The CYP2B6 Gene

The CYP2B6 gene and its variants (different forms) are studied in relation to chlorpyrifos (CPS), a broad-spectrum organophosphate insecticide. This substance is said to be neurotoxic to humans, which means it affects the nervous system. 

Chlorpyrifos oxon (CPO) is a toxic by-product of CPS metabolism and is produced by the CYP2B6. Two forms, CYP2B6 *5 and *8, convert chlorpyrifos to chlorpyrifos oxon.

CYP2B6*6 is another form of interest in the metabolism of chlorpyrifos. Studies suggest that CYP2B6*6 has increased activity but a reduced potential to activate chlorpyrifos in the human liver cells compared to other variants. Due to this, people with the *6 form of the CYP2B6 gene are less susceptible to chlorpyrifos toxicity.

The CYP2C19 Gene

The CYP2C19 gene has many forms, with CYP2C19*2 being the most common one. CYP2C19 acts as a catalyst in the metabolism of methoxychlor, a pesticide. However, in people having the non-functional form of the gene (also called poor metabolizers), the role of the CYP2C19 gene is performed by the CYP1A2 gene.

Variations in the PON1 Gene

The PON1 Gene

The PON gene family comprises three genes– PON1, PON2, and PON3. PON1 or Paraoxonase 1 is a calcium-dependent enzyme and is located on chromosome 7. This means that the activity of this enzyme depends upon the availability of calcium. There is increasing evidence from studies that variations in the PON1 gene increase an individual’s susceptibility to organophosphate toxicity (https://www.liebertpub.com/doi/10.1089/dna.2012.1961).

Organophosphates induce low-grade inflammation in humans, and PON1 gene variations have shown to cause intoxication in Cameroonian and Pakistani pollution (https://www.ias.ac.in/public/Resources/General/jgen/16-299-020217.pdf). Two variations or SNPs of this PON1 gene are essential in the metabolism of pesticides. These include rs662 and rs7493.

• rs662

Individuals having the T allele are said to be at a higher risk of developing organophosphate toxicity than those having the C allele.

Studies show that children with the C allele exposed to pesticides before their birth tend to have a greater abdominal circumference, more body fat content, high blood pressure, and BMI than those who have not been exposed. However, these features were not observed in children having TT genotype.

Recommendations To Boost Pesticide Detoxification

Prevent Inadvertent Exposure to Pesticides

Exposure to Pests

Avoiding exposure to pests by preventing their entry into your home, garden, and lawn is an excellent way to stay clear of any pesticides they have.

Non-Chemical Pest Control Methods

Since pesticides can cause toxicity, it is a good idea to use non-chemical pest control methods. Some of these options include natural pesticides, mechanical traps, sticky traps for more minor pests, and vacuuming during a flea infestation.

Follow Label Instructions While Using Pesticides

If you have to use pesticides, always read label instructions before you purchase the product. Then, follow the instructions on the label to use the pesticide. Always wear protective gear to avoid direct contact with the chemical, and make sure you prepare and use the pesticide away from food or other consumables.

Safe Storage and Disposal of Pesticides

The risk of exposure to pesticides is high even when you store them in your home. Ensure safe storage of pesticides in your house by keeping them under tightly closed containers. Keep them out of reach of children and yours. If your skin gets exposed to a pesticide, wash your hands properly. Always change your clothes or have a bath after working with pesticides to avoid any form of accidental inhalation of particles or their consumption.

How Genetic Testing Help In Removing Pesticides From Your System

If you are exposed to pesticides regularly due to your job or profession; it may be a good idea to get genetic testing done as individuals having the T allele in SNP rs662 are said to be at a higher risk of developing organophosphate toxicity as compared to those having the C allele. 

Summary

1. Pesticides are chemicals used in the agrochemical industry and at homes to kill, repel or mitigate pests.
2. Pesticides are of different types, based on their source.
3. Organochlorine and organophosphorus are commonly used pesticides.
4. Pesticides are harmful to the body as they alter enzyme activity and cause harmful effects to the nervous system. 
5. In addition, some pesticides have an affinity to get stored in the body’s fatty tissue. For this reason, they are regularly eliminated from the body.
6. Metabolism of pesticides in the body occurs in two phases – Phase I and Phase II.
7. The CYP and PON gene families are associated with the metabolism of pesticides.
8. Among the CYP family of genes, CYP2B6 and CYP2C19 play pivotal roles.
9. The PON1 gene and its variations are also said to affect the metabolism of organophosphate pesticides.
10. Avoiding pest exposure and storing and preparing pesticides safely can help limit pesticide exposure.
11. Individuals who work with pesticides regularly can get a genetic test to identify any high-risk genes associated with pesticide metabolism.

References

• https://www.ias.ac.in/public/Resources/General/jgen/16-299-020217.pdf 
• https://cdn.intechopen.com/pdfs/25674/InTechMetabolism_of_pesticides_b_human_cytochrome_p450_enzymes_in_vitro_a_survey.pdf
• https://www.health.ny.gov/environmental/pests/reduce.htm