CYP3A4 Gene - An Introduction

Cytochrome P450 Family 3 Subfamily A Member 4 or CYP3A4 gene belongs to the cluster of cytochrome P450 genes and is located on chromosome 7. 

The family of Cytochrome P450 gene gives instructions for the production of enzymes that are responsible for the metabolism (the process by which drugs are broken down or chemically altered by the body to bring about the effect) of drugs, hormones, and other xenobiotics (substances not produced by the body).

The CYP3A4 gene produces the CYP3A4 enzyme that belongs to a group of monooxygenases (enzymes that contain one oxygen atom). It is involved in the metabolism of nearly 50% to 60% of the currently prescribed drugs, including acetaminophen, codeine, cyclosporin A, diazepam, etc. 

The CYP3A4 gene is also involved in the production of cholesterol, steroids, and other lipids (fats). 

Along with the CYP3A5 gene, the CYP3A4 gene is found predominantly in the liver.

CYP3A4 Gene - The Different Metabolizer Types

There are over 20 variants (types) of the CYP3A4 gene that have been studied. Based on the presence of the CYP3A4 variant people carry, they can be classified as:

• Slow Metabolizers: People having at least one *22 allele of the CYP3A4 gene (CYP3A4 *22/*22 or CYP3A4*1/*22) are said to be poor metabolizers.

• Extensive Metabolizers: People having CYP3A4 *1/*1 allele are said to be extensive metabolizers.

• Ultra-rapid metabolizers: People who are carriers of CYP3A4*29 or CYP3A4*15 variants are said to be ultra-rapid metabolizers of quinine (an antimalarial drug). These individuals may have required higher doses of quinine for its required effect.

The *22, *1, *29, *15, etc., mentioned above are star alleles. Star alleles are used to name different haplotypes. A haplotype is a group of gene changes that are inherited together (CYP3A4*20, CYP3A4*1). 

Drugs That The CYP3A4 Acts On

• Immunosuppressants (ciclosporin, tacrolimus, sirolimus): These drugs suppress the immune system response and lower the body’s ability to reject an organ transplant.
• Chemotherapeutic drugs: Drugs or medicines used in chemotherapy for cancer treatment.
• Azole antifungals: A group of antifungals used to treat infections like thrust, candidiasis, tinea versicolor, athlete’s foot, jock itch, nail fungus, ringworm, etc.
• Macrolides: A type of antibiotic that includes commonly used drugs like erythromycin, clarithromycin, and azithromycin.
• Dapsone: A prescription medicine used to treat dermatitis herpetiformis and leprosy, usually in combination with rifampicin.
• Tricyclic antidepressants: Used to treat depression and various other conditions like obsessive-compulsive disorder, bedwetting, etc.
• Antipsychotics: These are drugs used to treat symptoms of psychosis - delusions, hallucinations, paranoia, confusion, etc. They may also be used to treat schizophrenia, severe depression, and anxiety.
• Opioids: A type of pain relief medication.
• Benzodiazepines: A class of drugs used to treat panic attacks, depression, insomnia, seizures, nausea, vomiting, and muscle cramps.
• Statins: Drugs used to lower bad cholesterol levels in the blood.
• Calcium channel blockers: Antihypertensive medications that are used to lower blood pressure levels.
• Sex hormones: Medications containing sex hormones like testosterone, estrogen, and progesterone used to treat hormonal imbalance.
• Glucocorticoids: Type of steroid medications used to fight inflammation in the body.

CYP3A4 Inducers And Inhibitors

Drugs that Induce CYP3A4 Activity

Inducers speed up the activity of the CYP3A4 enzyme, leading to quicker metabolism of the substances that the enzyme acts on. 

Some drugs that increase or induce CYP3A4 activity are:

• Phenobarbital: A long-acting barbiturate drug used as an anticonvulsant to treat all types of seizures.
• Phenytoin: An anti-epileptic drug used to control seizures.
• Rifampicin: An antibiotic used to treat bacterial infections, including tuberculosis.
• Many glucocorticoids: A type of steroid hormone that is used to reduce inflammation in the body.

Apart from drugs, some insecticides and pesticides are also known to induce CYP3A4 genes. These include 

• Endrin
• Some organochlorine pesticides like dichlorodiphenyltrichloroethane

Drugs that Inhibit CYP3A4 Activity

Inhibitors slow down the activity of the CYP3A4 enzyme, resulting in the slower metabolism of substances that the enzyme acts on.

Some drugs inhibit or reduce CYP3A4 activity, and these include:

• Clarithromycin: Used to treat bacterial infections like pneumonia, skin infections, etc.
• Diltiazem: Used to treat high blood pressure and angina.
• Erythromycin: An antibiotic used to treat bacterial infections
• Itraconazole: An antifungal medication used to treat fungal infections, including aspergillosis, blastomycosis, and histoplasmosis.
• Ketoconazole: Antifungal medication
• Ritonavir: Antiviral medication used to treat HIV/AIDS
• Verapamil: Used to treat hypertension (high blood pressure)
• Cimetidine: Used in the treatment of heartburn and peptic ulcers.

CYP3A4 gene inhibitor drugs can be classified based on their potency as – strong, moderate, or weak inhibitors.

Variations In The CYP3A4 Gene 

CYP3A4 has fewer variants (types) than other CYP genes, and only a few of them are known to affect enzyme function. There are around 20 variants of this gene that have no clinical significance. Few significant variants include CYP3A4 *22, *1B, and *18B.

CYP3A4*22

Also referred to as rs35599367, people with the T allele of this haplotype show decreased CYP3A4 enzyme activity. This haplotype is found in 4% to 8% of the population.

Studies show that people with T/T allele had two times lower enzyme activity than those with the C allele. This is important because people having the T/T genotype require a 40% lower dose of simvastatin (a cholesterol-lowering drug).

Children with the CYP3A4*22 variant show improved asthma control by taking fluticasone propionate (a drug used to treat asthma).

Research also states that CYP3A4*22 carriers were less likely to suffer from severe hot flashes on taking tamoxifen therapy (used for breast cancer).

CYP3A4*1B

rs2740574 is a single nucleotide polymorphism or SNP in the CYP3A4 gene. The presence of the G allele in this SNP in this gene is known as CYP3A4*1B.

The *1B haplotype may be associated with methadone overdose and fatal intoxication. 

The G allele of this haplotype also increases the risk for prostate, ovarian, and lung cancers.

CYP3A4*18B

Also denoted as rs2242480, this variant of the CYP3A4 gene affects fentanyl (an opioid pain medication) dosage. Research states that patients with *18B/*18B alleles required lesser fentanyl dosage to control pain than patients with *1/*1 genotype.

Recommendations To Boost CYP3A4 Metabolism

Food and Herbal Medications

Some interactions of the CYP3A4 gene with herbal medicines and food can reduce its metabolic effect. 

• Dietary supplements
• Goldenseal (Hydrastis Canadensis): A herbal supplement used to prevent cold and upper respiratory tract infections. 
• Black pepper: A commonly used spice that acts as a CYP3A4 inhibitor.
• Schisandra (prepared from woody vines of Schisandra species): It is used in traditional Chinese medicine. It is known to increase blood levels of CYP3A4 substrates if you are taking any.
• Grapefruit: This is a strong inhibitor of the CYP3A4 enzyme and may cause adverse effects.

Therefore, most doctors take a thorough history of all medications, herbal supplements, or alternative medicines that you may be taking to avoid any adverse reactions and prevent reduced CYP3A4 metabolism. 

Genetic Testing

Genetic testing may be advised before prescribing drugs that are metabolized by the CYP3A4 gene. This is particularly true while prescribing simvastatin, fluticasone propionate (in children), tamoxifen, methadone, and fentanyl.

Summary

1. The CYP3A4 gene is part of the Cytochrome P450 family of genes and is located on chromosome 7.
2. The CYP3A4 enzyme is found predominantly in the liver and is participates in the metabolism of nearly 50%-60% of commonly used drugs.
3. The CYP3A4 enzyme plays a role in the synthesis of cholesterol, steroid, and lipids.
4. The CYP3A4 enzyme acts on a wide range of drugs and substrates, many of which are inducers of the gene, while the rest are inhibitors.
5. The most significant variants of the CYP3A4 gene include *22, *18B, and *1B.
6. Genetic testing for the CYP3A4 gene may be helpful for doctors to determine the appropriate dosage of some drugs based on the variant you may have.

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