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The CYP2A6 enzyme is a part of the Cytochrome P450 (CYPs) family. The CYP family is a group of enzymes that play a major role in detoxification in the body. 

This enzyme helps in the metabolism and clearance of the various endogenous (produced internally) and exogenous (produced externally) substances. 

The CYP2A6 enzyme is predominantly found in the liver cells and forms 4% of the total CYP family. This enzyme is also found in the lung, trachea, nasal mucosa, breast, and sex organs. 

The CYP2A6 gene is said to be highly polymorphic, i.e., it has many variations (or types), and each variation affects enzyme activity.

There are over 40 known types of this gene including, CYP2A6*2, CYP2A6*4, and CYP2A6*6 (The *2, *4, and *6 are star alleles, which is the labeling method of haplotypes - a combination of multiple changes in a gene). 

The activity of the CYP2A6 enzyme is influenced by genetics, drugs, and other environmental factors, which in turn affects the detoxification process in the body. 

CYP2A6 - The Different Metabolizer Types

Slow or Poor Metabolizers – These are people who produce no or very little of the CYP2A6 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.  

Individuals with CYP2A6 *2, *4, *9, and *12 are said to be slow metabolizers of nicotine. These individuals are less likely to be smokers, show lower levels of dependence, smoke fewer cigarettes per day, take smaller puff volumes, and are more likely to quit the habit. They are also more likely to benefit from nicotine replacement therapy. 

Intermediate Metabolizers – These people produce moderate amounts of the CYP2A6 enzyme. 

Rapid Metabolizers – These people have excess CYP2A6 enzyme activity. Drugs are metabolized very quickly and cleared from the body rapidly. This reduces the effectiveness of the drugs. 

CYP2A6*1 type is associated with rapid metabolism. Rapid metabolizers tend to smoke more cigarettes per day. These individuals are also more dependent on nicotine compared to other groups having the *2, *4, and other alleles. 

Compounds That The CYP2A6 Gene Act On

The CYP2A6 enzyme participates in Phase I of detoxification and is involved in the processing and clearance of many endogenous and exogenous compounds. These include:

Therapeutic drugs

Environmental Toxins


Substances that can become cancer-causing agents after undergoing modification(s).

Endogenous Compounds

The effects produced by the CYP2A6 enzyme are substrate-specific, which means the gene activity and by-products vary for each substrate it acts on. 

The CYP2A6 gene has been extensively studied in association with its nicotine metabolism as it is said to influence smoking behavior and addiction. 

CYP2A6 and Nicotine

Approximately 80% of nicotine in the body is eliminated by the CYP2A6 enzyme. For this reason, there is a clear link between CYP2A6 genotypes, smoking behavior, and lung cancer risk. CYP2A6 participates in the two-step process, which converts nicotine to cotinine. 

The rate at which nicotine is metabolized in the body is influenced by the CYP2A6 gene. This directly affects the nicotine levels in the blood. 

Factors that inhibit (or hinder) the activity of CYP2A6 are important as they can supplement anti-smoking therapy. Individuals who have an inactivated CYP2A6 gene due to certain changes are slow at converting nicotine into cotinine and are called slow-metabolizers. 

Due to the slow metabolism and clearance of nicotine, their blood nicotine levels are high, and they are less likely to be smokers. If they are smokers, they tend to smoke fewer cigarettes per day, take smaller puff volumes, have lower levels of dependence, are more able to quit, and benefit more from regular and extended nicotine patch replacement therapy compared to normal metabolizers.

Increased CYP2A6 activity increases the metabolism of nicotine, and these individuals are likely to smoke more cigarettes in a day.

CYP2A6 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 CYP2A6 Activity

Drugs that Inhibit CYP2D6 Activity

Variations in the CYP2A6 gene

CYP2A6*2Decreased enzyme activity
CYP2A6*5Decreased enzyme activity
CYP2A6*6Decreased enzyme activity
CYP2A6*7Decreased enzyme activity
CYP2A6*9Decreased enzyme activity
CYP2A6*17Decreased enzyme activity
CYP2A6*18Decreased enzyme activity
CYP2A6*23Decreased enzyme activity
CYP2A6*25Decreased enzyme activity
CYP2A6*26Decreased enzyme activity
CYP2A6*35Decreased enzyme activity
CYP2A6*39Decreased enzyme activity

A haplotype is a group of gene changes that are inherited together.  The *2, *5, *6, *7, etc., star alleles. Star alleles are used to name different haplotypes. 

Recommendations for Optimal CYP2A6 Activity

Consume Grapefruit Juice And Cinnamon With Caution

Reduced CYP2A6 enzyme levels are beneficial for smokers who are trying to quit the habit. But, consuming CYP2A6 inhibitor substances like grapefruit juice and cinnamon can further slow down CYP2A6 gene activity. When slow metabolizers consume these substances, it affects their ability to metabolize certain drugs. On the other hand, it can be helpful for fast metabolizers.

It is recommended to consume CYP2A6 inhibitors with caution and upon consulting a qualified medical practitioner. 

Genetic Testing

Genetic testing for abnormal changes in the CYP2A6 gene is important as it can help prescribe appropriate smoking cessation drugs to smokers who are looking to quit the habit. Varenicline is a smoking cessation drug that is more effective in people with normal CYP2A6 function (and fast metabolizers). Similarly, the smoking cessation drug Bupropion is not recommended in slow metabolizers but is three times more effective.


  1. CYP2A6 gene is a part of the Cytochrome P450 family of genes responsible for detoxification in the body.
  2. There are over 40 types of CYP2A6 gene, and each type influences enzyme activity.
  3. The activity of the CYP2A6 gene is influenced by genetics, environmental factors, and certain drugs.
  4. The CYP2A6 gene has many substrates, but nicotine is the most extensively studied one. 
  5. Certain changes in the CYP2A6 gene reduce the enzyme activity and result in the slow metabolism of nicotine.
  6. Getting a genetic test is recommended in smokers who are trying to quit the habit so that the right smoking cessation drugs can be prescribed to them.


Pharmacogenomics, sometimes called as pharmacogenetics, is the study of how genes affect a person’s response to drugs. It is a combination of two fields - pharmacology (the science of drugs) and genomics (the study of genes and their functions). 

Just like how genes determine our eye color, height, etc. they also partly influence how our body responds to drugs. Some chemical changes in these genes can elicit unwanted side effects upon drug consumption.

The long-term goal of pharmacogenomic research is to design drugs best suited for each person, in order to avoid these undesirable side effects. 

The Importance of Pharmacogenomics

Genes influence multiple steps involved in your response to drugs. They include:

Drug Receptors: Some drugs require a type of protein called the receptors, to which they bind and get activated. Your genes can influence the number and effectiveness of these receptors.

Example: T-DM1 is a drug used to treat breast cancer. This drug works by attaching to a receptor called the HER-2 receptor. However, not all breast cancer cells express this receptor. So, this drug may not be effective for all individuals with breast cancer. 

Drug Uptake: Certain drugs are activated only after they are taken into the cells and tissues. If your genetic makeup leads to reduced uptake of the drug, it may accumulate in other parts of the body. 

Example: Statins are a class of drugs commonly used to treat high cholesterol levels. For the drug to work, it must be transported to and taken up by the liver efficiently. SLCO1B1 gene influences this process. A change in this gene results in a reduced transport of statins to the liver. This can result in statin buildup in muscles resulting in pain and weakness. 

Drug breakdown/metabolism: If your genetic makeup results in a faster breakdown of drugs, it gets clear from the body faster. This may warrant an increased dosage of the drug or a different drug. On the other hand, if your drug metabolism is slow, it stays in your body for a longer period. In this case, a lower dosage may do the work. 

Example: Amitriptyline is an antidepressant drug. Two genes, namely, CYP2D6 and CYP2C19, are involved in its metabolism. If you carry a change that slows down or boosts the metabolism, you may need to alter the drug dosage accordingly. 

Patients can respond differently to the same medicine. 

Commonly used drugs to treat some medical conditions need not be effective for everyone. Some examples are:

- Antidepressants drugs (SSRIs) are ineffective in as many as 38% of patients who are prescribed these drugs 

- Asthma drugs are ineffective in as many as 40% of patients who are prescribed these drugs 

- Diabetes drugs are ineffective in as many as 43% of patients who are prescribed these drugs 

- Arthritis drugs are ineffective in as many as 50% of patients who are prescribed these drugs 

- Alzheimer’s drugs are ineffective in as many as 70% of patients who are prescribed these drugs

- Cancer drugs are ineffective in as many as 75% of patients who are prescribed these drugs

- Cardiac Arrhythmias drugs are ineffective in as many as 40% of patients who are prescribed these drugs

Source: Brian B Spear, Margo Heath-Chiozzi, Jeffrey Huff, Clinical application of pharmacogenetics, Trends in Molecular Medicine, Volume 7, Issue 5, 2001, Pages 201-204, ISSN 1471-4914,

What Can a Pharmacogenomics Test reveal?

The purpose of pharmacogenomic testing is to find out if a medication is right for you. A pharmacogenomic test will help in knowing:

Efficacy - Whether a medication may be an effective treatment for you. 

Dosage - What is the best dose for you for specific medications. 

Toxicity - Whether you could have serious side effects from a medication.

CYP gene and Drug Responses

CYP enzymes or the Cytochrome P450 enzymes are the major drug-metabolizing enzymes in the body. The P450 enzymes contain a protein called heme (iron-containing compound) and are commonly present in hepatocytes (cells of the liver). This is why drugs are mostly broken down or metabolized in the liver. 

From a clinical perspective, the most commonly tested CYPs are:

- CYP2D6

- CYP2C9

- CYP2C19

- CYP3A5

Changes in CYP enzymes can influence the metabolism and clearance of drugs.
The CYP450 Test categorizes individuals into one of the four known metabolic profiles, called “predicted phenotypes.”

What are the limitations of a CYP test?

- Pharmacogenomic research is still in its infancy. Therefore, tests are available only for certain drugs.

- Any change in medication will require a new CYP test - this is because different enzymes are responsible for metabolizing different drugs

- The test reveals how genes affect the drugs and not what the drug does to the body (for example, we cannot determine how the drugs change certain receptors in the brain to alleviate the symptoms)

- Some drugs are metabolized and cleared by more than one CYP enzyme. For example, antidepressant drugs like the SSRIs (Selective Serotonin Reuptake Inhibitor) are metabolized by serotonin receptor molecules as well. This can limit the predictive value of the test.

Who should take the PGx test ?

If you answer yes to any of the below questions, you are an ideal candidate for a PGx test.

1. Are you currently taking four or more medications monthly?  

2. Have you or anyone in your family ever been hospitalized for taking medication?  

3. Have you or anyone in your family ever felt ill after taking a new medication?  

4. Has your doctor changed your dose of medication due to a lack of response or a reaction to the medication?  

5. Do you take your prescribed medication, and you still aren’t feeling better?

6. Are you taking or is your doctor considering prescribing to you pain medicine, tamoxifen, or Plavix?  

7. Do you take herbal supplements regularly in addition to your medication?  

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  2. Brian B Spear, Margo Heath-Chiozzi, Jeffrey Huff, Clinical application of pharmacogenetics, Trends in Molecular Medicine, Volume 7, Issue 5, 2001, Pages 201-204, ISSN 1471-4914,
  3. Ingelman-Sundberg M. Trends in Pharmacol Sci 2004;25(4):193-200
  4. Mrazek DA.Curr Psych Online 2004;3(9). Retrieved September 17, 2006
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