CYP2J2 Gene - An Introduction

The CYP2J2 gene contains instructions for the production of the cytochrome P450 2J2 enzyme. This enzyme is found in the extrahepatic tissues (tissues located outside the liver), especially in the gastrointestinal tract, kidneys, lungs, pancreas, and brain. 

The CYP2J2 enzyme is called an oxygenase. This is because it breaks down xenobiotics (substances not usually expected to be found in the body), cholesterol, fatty acids, and numerous other chemicals by adding an oxygen molecule to them. 

CYP2J2 is especially important in arachidonic acid (AA) metabolism. AA is a polyunsaturated omega-6 fatty acid found in organ meat, poultry, eggs, seafood, and seaweed. 

The CYP2J2 enzyme converts AA into four epoxyeicosatrienoic acids (EETs). EETs are types of signaling molecules that have various positive effects on the body.

EETs may be able to:

• Protect the heart by controlling inflammation, preventing the formation of blood clots, and dilating blood vessels
• Bring down the risk of strokes by reducing blood pressure
• Protect the brain and heart from ischemia (decreased blood and oxygen flow)
• Prevent insulin resistance and benefit people with type I and type II diabetes
• Bring down pain intensity

Drugs That The CYP2J2 Gene Acts On

The CYP2J2 enzyme metabolizes many drugs.

Ebastine

Ebastine is an antihistamine drug used to treat signs of allergies, including sneezing, swelling, itching, and rashes. 

Astemizole

Astemizole is also an antihistamine drug that provides long-term relief to allergy symptoms.  

Terfenadine

Terfenadine is also an antihistamine drug used to treat allergic symptoms.

Diclofenac

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) used to treat inflammatory conditions like gout and arthritis. 

Perphenazine

Perphenazine is an antipsychotic drug used in treating mood disorders, including schizophrenia, bipolar disorder, and symptoms like hallucinations and aggressive behavior. 

Bufuralol

Budurarol is a non-selective adrenoceptor blocking agent that has antiarrhythmic properties. It reduces heart rate, stabilizes blood pressure, and helps protect cardiac health. 

Doxorubicin 

Doxorubicin is an anti-cancer drug and is used in chemotherapy. Doxorubicin, in higher doses, may lead to cardiotoxicity and heart failure. Studies show that higher levels of CYP2J2 enzyme may prevent doxorubicin toxicity and protect the heart. 

CYP2J2 - 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 CYP2J2 Activity

Inducers speed up the activity of the CYP2J2 enzyme, leading to quicker metabolism of the xenobiotics and drugs that the enzyme acts on. As a result, the drugs don’t get enough time to work.

Here is a list of drugs that induce CYP2J2 activity.

• Rosiglitazone - This is an antidiabetic medication that improves insulin sensitivity. The drug can induce CYP2J2 activity by up to 50%.
• Carbamazepine - Carbamazepine is an anticonvulsant medication. It helps prevent seizures. The drug can cause a 30% increase in enzyme activity. 

Drugs That Inhibit CYP2J2 Activity

Inhibitors slow down the activity of the CYP2J2 enzyme, resulting in slower metabolism of xenobiotics and drugs that the enzyme acts on. As a result, the drug stays in circulation for a longer time, and there is an increased risk of a drug overdose.

Here is a list of drugs that inhibit CYp2J2 activity.

• Danazol - Danazol is a class of androgenic hormones that are used to treat problems like endometriosis (endometrium grows outside the uterus), inherited angioedema (swelling of the area below the skin), and non-cancerous cysts development in the breasts (Fibrocystic Breast Disease). Danazol can inhibit CYP2J2 activity by up to 95%.
• Ketoconazole - Ketoconazole is an antifungal medication used to treat a variety of fungal infections. 
• Astemizole - Astemizole is an antihistamine medication that offers long-term relief from allergy symptoms.
• Cisapride - Cisapride is used to treat the symptoms of Gastroesophageal Reflux Disease (GERD)
• Pimozide - Pimozide is an antipsychotic drug used to treat Tourette’s syndrome (a nervous system disorder that causes people to make repetitive actions and sounds). About 10 μM of pimozide can reduce CYP2J2 activity by up to 60%.

Types of CYP2J2 Gene

CYP2J2*7 haplotype

There are many types or variations of CYP2J2, the most well-studied being the CYP2J2*7 haplotype. 

A haplotype is a group of gene changes that are inherited together. *7 is called a star allele. Star alleles are used to name different haplotypes.

A study shows that in the Caucasian population, the CYP2J2*7 allele leads to a 40% reduction in the CYP2J2 enzyme levels. This can increase the risk of developing cardiovascular diseases like myocardial infarction, ischemic stroke, and atherosclerosis. 

rs10889160 and rs11572325 SNPs

Two Single Nucleotide Polymorphisms (SNPs) - rs10889160 and rs11572325 in this gene have been associated with an increased risk of myocardial infarction. 

People with the G and A alleles of the SNPs rs10889160 and rs11572325, respectively, have a 1.24 and 1.27-fold increased risk of developing myocardial infarction than those with the A and T alleles.

rs1155002 and rs2280274 SNPs

A case-controlled study analyzed the relationship between variations in the CYP2J2 gene and the risk of developing Chronic Obstructive Pulmonary Disease (COPD).

People with the T allele of the SNP rs1155002 had an increased risk of developing COPD, while people with the T allele of the SNP rs2280274 had a decreased risk. 

In addition, being a female and smoking further increased the risk.

Recommendations To Boost CYP2J2 Metabolism

Butylated Hydroxyanisole (BHA) Usage

BHA is a preservative added to many food products. It is a food-based antioxidant to prevent oxidative damage to oils and fats. It keeps oil and fat-based foods fresher for a longer time. BHA is found in foods like the below.

• Cereal
• Chips
• Preserved meat
• Chewing gum
• Butter
• Packaged and baked goods

BHA can induce CYP2J2 activity. Therefore, if you are on drugs metabolized by CYP2J2, limit intake of the above foods to prevent faster metabolism of the drugs. 

Be Aware Of Drugs That Inhibit CYP2J2 Activity

If you are on specific drugs that inhibit CYP2J2 activity, consult your doctor and understand the effects on the body. Combining medications metabolized by the CYP2J2 enzyme and these CYP2J2 inhibitors may lead to a drug overdose.  

Genetic Testing

Genetic testing will help understand how protective the CYP2J2 gene variations are against cardiovascular diseases. This can play a role in predicting heart conditions in the future. 

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Summary

1. The CYP2J2 gene provides instruction for the production of the CYP2J2 enzyme. This enzyme plays a role in the metabolism of different xenobiotics, drugs, fatty acids, and lipids. 
2. The CYP2J2 enzyme is essential for arachidonic acid (a type of omega-6 fatty acid) metabolism. It converts arachidonic acid into four epoxyeicosatrienoic acids (EETs).
3. EETs are beneficial to the body and help protect heart and brain health, reduce inflammation, prevent insulin resistance, and reduce blood pressure.
4. The CYP2J2 gene helps in the metabolism of drugs like ebastine, astemizole, terfenadine, diclofenac, and Bufuralol. 
5. Drugs like Rosiglitazone and Carbamazepine can induce CYP2J2 activity and lead to faster metabolism of drugs that the enzyme acts on. 
6. Drugs like Danazol, Ketoconazole, Astemizole, Cisapride, and Pimozide inhibit CYP2J2 activity and can lead to a drug overdose.
7. Specific CYP2J2 gene changes can increase or decrease a person’s risk of developing cardiovascular conditions and Chronic Obstructive Pulmonary Diseases.
8. If you are on drugs that inhibit CYP2J2 activity, talk to your doctor to understand how they may affect your body.
9. Genetic testing will help predict cardiovascular problems in individuals and help take preventive action. 

References

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086341/
• https://go.drugbank.com/drugs/DB06726
• https://pubmed.ncbi.nlm.nih.gov/15861034/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200477/
• https://dmd.aspetjournals.org/content/46/8/1053#sec-13
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834129/
• https://www.mdpi.com/1422-0067/19/7/1916/htm
• https://www.uniprot.org/uniprot/P51589
• https://pubmed.ncbi.nlm.nih.gov/30378391/
• https://en.wikipedia.org/wiki/CYP2J2#Function  https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/cyp2j2
• https://dmd.aspetjournals.org/content/46/8/1053

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