Gene Talk
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Gene Talk

How The CYP2A6 Gene Influences Detoxification

How The CYP2A6 Gene Influences Detoxification

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

- Valproic acid: Used to treat epilepsy, bipolar disorder and prevent migraine headaches
- Pilocarpine: Used to treat dry mouth conditions by increasing saliva production. It is also used in eye drops to reduce pressure in the eyes
- Tegafur: Used as an anticancer drug that is used in combination with other anticancer medications to treat gastric and colorectal cancers
- Fadrozole: Used to treat breast cancer
- Ifosfamide: Used in chemotherapy to treat different types of cancers
- Cyclophosphamide: A chemotherapy medication that is also used as an immunosuppressant
- Nicotine: Used as a smoking cessation product to help relieve withdrawal symptoms
- Tamoxifen: An estrogen receptor modulating drug used in the treatment of breast cancer in men and women
- Promazine: An antipsychotic medication used to treat schizophrenia
- Propofol: A short-acting general anesthetic agent used to start and maintain general anesthesia

Environmental Toxins

- Gasoline

Procarcinogens

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

- Nitrosamines
- Aflatoxin

Endogenous Compounds

- Retinoic acid
- Steroids

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.

- First, nicotine is converted to the nicotine iminium ion
- Next, nicotine iminium ion is metabolized (or broken down) into 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

- Phenobarbital — Used in the treatment of some types of epilepsies
- Dexamethasone — A corticosteroid medication used to treat rheumatic problems, severe allergies, skin conditions, asthma, and chronic obstructive lung disease.
- Rifampicin — An antibiotic used in the treatment of tuberculosis.

Drugs that Inhibit CYP2D6 Activity

- Methoxsalen — Used in the treatment of psoriasis, eczema, vitiligo, and skin-related lymphomas (cutaneous lymphomas)
- Selegiline — Used in the treatment of Parkinson’s disease and Major Depressive Disorder.

Variations in the CYP2A6 gene

HaplotypeEffectCYP2A6*2Decreased enzyme activityCYP2A6*5Decreased enzyme activityCYP2A6*6Decreased enzyme activityCYP2A6*7Decreased enzyme activityCYP2A6*9Decreased enzyme activityCYP2A6*17Decreased enzyme activityCYP2A6*18Decreased enzyme activityCYP2A6*23Decreased enzyme activityCYP2A6*25Decreased enzyme activityCYP2A6*26Decreased enzyme activityCYP2A6*35Decreased enzyme activityCYP2A6*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.

Summary

- CYP2A6 gene is a part of the Cytochrome P450 family of genes responsible for detoxification in the body.
- There are over 40 types of CYP2A6 gene, and each type influences enzyme activity.
- The activity of the CYP2A6 gene is influenced by genetics, environmental factors, and certain drugs.
- The CYP2A6 gene has many substrates, but nicotine is the most extensively studied one.
- Certain changes in the CYP2A6 gene reduce the enzyme activity and result in the slow metabolism of nicotine.
- 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.

References

- https://pubmed.ncbi.nlm.nih.gov/22706231/
- https://www.nature.com/articles/6500481
- https://www.pharmgkb.org/literature/8237190
- https://www.pharmgkb.org/literature/8454024
- https://www.pharmgkb.org/literature/15023663
- https://www.sciencedirect.com/science/article/pii/B9780128002124000960
- https://pubmed.ncbi.nlm.nih.gov/10899369/
- https://www.sciencedirect.com/topics/neuroscience/cyp2a6
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748630/
- https://www.pharmgkb.org/vip/PA166169430/overview
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427481/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748630/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427481

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