CYP3A5 Gene – An Introduction
CYP3A5 belongs to the CYP3A subfamily of genes of the cytochrome P450 family responsible for the processing and elimination (or clearance) of drugs.Â
The CYP3A subfamily is the most abundant CYP gene found in the liver and the intestines. This subfamily is associated with eliminating nearly 37% of 200 of the most commonly prescribed drugs.
Along with CYP3A4, the CYP3A5 gene makes up for around 30% of the cytochrome P450 activity in the liver.
CYP3A5 Gene – The Different Metabolizer Types
Depending on the levels of the CYP3A5 enzyme, people can be classified into the following metabolizer groups:
- Extensive Metabolizers: People with two normal copies (*1/*1) of the CYP3A5 gene are said to be normal metabolizers and have an active CYP3A5 enzyme.
20% of African-Americans and less than 1% of Europeans are found to be normal metabolizers of the CYP3A5 gene.
- Intermediate Metabolizers: Individuals with one normal copy and one decreased function copy of the CYP3A5 gene, i.e., *1/*3, *1/*6, or *1/*7, are said to be intermediate metabolizers.
The CYP3A5 enzyme activity in these people is said to be lower than in normal metabolizers. In these individuals, the doctor may increase the medication dose.
Around 50% of African-Americans and 15% of people of European descent are said to be CYP3A5 intermediate metabolizers.
- Poor Metabolizers: Individuals with two decreased function copies of the CYP3A5 gene (*3/*3, *6/*6, *7/*7, *3/*6, *3/*7, *6/*7) are said to be poor metabolizers. They have low CYP3A5 enzyme levels.
The medication dosage need not be altered for such people since most of the medications have been developed for poor metabolizers.
Around 30% African-Americans and 85% people of European descent are said to be poor metabolizers.
Normal and intermediate metabolizers are said to be a high-risk group and require a change in their medicine dosage based on their CYP3A5 gene.
However, poor metabolizers fall under a low-risk group and do not require any alteration in their existing medicine dosage.
Drugs That The CYP3A5 Acts On
- Cyclosporine: An immunosuppressant drug used in bone marrow and organ transplants. It is also used in conditions like ulcerative colitis, rheumatoid arthritis, and atopic dermatitis to reduce inflammation.
- Quinine: An antimalarial drug that is also used in treating other conditions like nocturnal leg cramps and other muscular disorders.
- Vincristine: An anti-cancer drug that is used in the treatment of acute leukemia, malignant lymphoma, Hodgkin’s disease
- Midazolam: A short-acting hypnotic drug used to treat anxiety, bring about muscle relaxation, and as a sedative. It is also used as a sedative before surgery to induce anesthesia.
- Tacrolimus: An immunosuppressant drug primarily used following an organ transplant surgery to reduce the patient’s immune response and lower the risk of organ rejection.
Though the metabolism of this drug is primarily mediated by the CYP3A4 gene, the CYP3A5 gene participates in the process. Individuals having the normal variant (or type) of the CYP3A5 gene are said to be extensive metabolizers of this drug and require higher doses of tacrolimus for the desired effect.
- Indinavir: An antiviral drug used in the treatment of HIV.
CYP3A5 Inducers And Inhibitors
Drugs that Induce CYP3A5 Activity
Some drugs induce or increase the activity of the CYP3A5 gene, and these include:
- Phenobarbital: A long-acting barbiturate drug used as an anticonvulsant to treat all types of seizures
- Rifampicin: An antibiotic that is used as a first-line drug to treat tuberculosis
- Carbamazepine: An anticonvulsant drug used to treat epilepsy and relieve pain associated with trigeminal neuralgia
- Enzalutamide: An androgen receptor inhibitor used in castration-resistant prostate cancer cases
Drugs that Inhibit CYP3A5 Activity
Commonly prescribed drugs that inhibit CYP3A5 activity include:
- Isavuconazole: An antifungal medication used in the treatment of invasive aspergillosis
- Verapamil: A calcium-channel blocker drug that is commonly used to treat angina, cardiac arrhythmia, and hypertension (high blood pressure)
- Ciprofloxacin: Used to treat bacterial infections
- Cimetidine: Used to control acidity and related disorders as it inhibits the production of gastric acid
- Erythromycin: An antibiotic used in the treatment of bacterial infections
Variations In The CYP3A5 Gene
The CYP3A5 gene is polymorphic, i.e., it has multiple variants. There are over 25 allelic variants of this gene.
| Haplotype | Effect |
| CYP3A5*3 | Inactive (non-functional variant) |
| CYP3A5*6 | Inactive (non-functional variant) |
| CYP3A5*8 | Decreased enzyme activity |
| CYP3A5*9 | Decreased enzyme activity |
| CYP3A5*10 | Decreased enzyme activity |
A haplotype is a group of gene changes that are inherited together. The *3, *4, *14, *41, etc., star alleles. Star alleles are used to name different haplotypes.
The normal functioning allele is numbered as CYP3A5*1. The *3 variant is the most common and frequently studied. The other most studied alleles include the *6 and *7.
CYP3A5*3 and CYP3A5*1
CYP3A5*3 is the most frequent and well-studied variant allele of CYP3A5. It is a non-functional variant.
Individuals with the *1/*1 or *1/*3 types can metabolize certain substrates of the CYP3A5 gene better than those with the *3/*3 type. This has been studied in relation to the drug Tacrolimus (used to prevent rejection following organ implantation).
Individuals having *1/*1 variant of the gene have a higher clearance of the drug than those having other variants. When tacrolimus is prescribed, its concentration must be high enough to prevent transplant rejection but low enough to avoid toxicity.
Though the relation between clearance of tacrolimus and activity of the CYP3A5 gene has been established, this link has not proved to play an active role in organ rejection following a transplant procedure. Â
Individuals with the *1/*3 variant show rapid clearance of saquinavir, an antiviral drug, compared to people with the *3/*3 allele.
In pediatric patients treated with vincristine for precursor B cell acute lymphoblastic leukemia, children with *1/*1 and *1/*3 showed lesser treatment-related neurotoxicity.
Another group of drugs that the CYP3A5 gene acts on is statins or lipid-lowering drugs. According to one study, statin drugs like lovastatin, simvastatin, and atorvastatin were less effective in people with *1/*1 and *1/*3 carriers than those with *3/*3.Â
In another study, individuals with *3/*3 developed myalgia and were more likely to suffer from muscle damage as a side-effect of statin treatment compared to the other two types *1/*1 and *1/*3.
The *3 variation in the CYP3A5 gene is also associated with an increased risk of developing certain diseases. According to a study, it was found that Asian Indians carrying the *3 variant of the gene showed an increased risk of developing CML or Chronic Myeloid Leukaemia.
In another study conducted on Japanese women, it was found that CYP3A5 expressors, i.e., those who are *1/*1 and *1/*3 carriers, had a higher risk of developing breast cancer as compared to those having the *3/*3 variant of the gene.
CYP3A5*6
This variant is more common in individuals with African-American lineage than Caucasians and Asians. The presence of this variant indicates no gene activity, making the individual a non-expressor of the gene.Â
A study was conducted to determine the level of tamoxifen (a drug used in the treatment of breast cancer) and side effects in people carrying the *3 and *6 variants.
Though there was no difference found in the clearance or effectiveness of the drug, there was a significant difference in the tumor size in women having the *6 variant as compared to those without this variant.
CYP3A5*7
This variant of the CYP3A5 gene is found in around 8% of the African population but has not been found in Caucasians. Since this variant reduces the activity of the CYP3A5 gene, it is called the non-functional variant. Similar to the *3 and *6 variants, having the *7 variant proved beneficial to Brazilian kidney transplant recipients. However, further research is required in this regard.
Recommendations To Boost CYP3A5 Metabolism
Genetic Testing
Individuals who require organ or bone marrow transplants must be advised to undergo genetic testing to determine the status of the CYP3A5 gene. This will help their healthcare provider adjust the immunosuppressant dosage to avoid organ rejection.
Dose Adjustment for Patients Taking Tacrolimus
- In extensive and intermediate metabolizers, the starting dose of tacrolimus should be 1.5 to 2 times the recommended starting dose, but the total starting dose must not exceed 0.3mg/kg/day.
- In poor metabolizers, the therapy with tacrolimus drug is started with the standard recommended dose.
- In patients undergoing a liver transplant, the genotype of the donor and the recipient’s liver CYP3A5 gene may not be the same. In these cases, the doctor must consider the genotypes of both the donor and the recipient before determining the dose of tacrolimus.
Watch Out For Drug Interactions
While prescribing tacrolimus in transplant patients, interactions with other drugs prescribed in these patients, like calcium channel blockers and azole antifungals, must be considered.
In individuals having the *1/*1 genotype, the interaction of tacrolimus with the azole antifungals was found to be less profound compared to other types.
Summary
- The CYP3A5 gene is responsible for the processing and elimination of nearly 37% of the 200 most commonly prescribed drugs.
- Based on the CYP3A5 gene variants, individuals can be broadly grouped under three categories – extensive metabolizers, intermediate metabolizers, and poor metabolizers.
- Some drugs that the CYP3A5 gene acts on include cyclosporine, quinine, vincristine, midazolam, and tacrolimus.
- Some CYP3A5 inducers are phenobarbital, rifampicin, carbamazepine, and enzalutamide.
- Drugs that inhibit the activity of the CYP3A5 enzyme are isavuconazole, verapamil, ciprofloxacin, cimetidine, and erythromycin.
- Haplotype *1/*1 is said to be the normal variant, and individuals with this genotype are said to be expressors of the CYP3A5 gene.
- People with non-functional variants like *3, *6, and *7 are called non-expressors of the gene.
- People who require an organ transplant must undergo genetic testing to determine the activity of their CYP3A5 gene. Their genotype helps their healthcare provider decide the dosage of immunosuppressant drugs like tacrolimus.
References:
- https://pubmed.ncbi.nlm.nih.gov/15689501/
- https://pubmed.ncbi.nlm.nih.gov/21671989/
- https://www.pharmgkb.org/vip/PA166170041
- https://pubmed.ncbi.nlm.nih.gov/16338276/
- https://pubmed.ncbi.nlm.nih.gov/15284534/
- https://pubmed.ncbi.nlm.nih.gov/21039054/
- https://pubmed.ncbi.nlm.nih.gov/11279519/
- https://www.snpedia.com/index.php/Rs10264272
- https://pubmed.ncbi.nlm.nih.gov/15596297/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481158/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481158
