Cytochrome P450 Genetics

Kortney Manning, Pharm.D. Candidate

A cytochrome is the name given to a number of compounds that have similar structural elements and perform various chemical reactions in the body. Cytochrome P450, or CYP450 for short, is a group of enzymes that are responsible for many metabolic processes in the body. P450 describes the wavelength of light (450 nanometers) that is absorbed by these compounds. It is mainly known for the metabolism of many drugs that are commonly used to treat various illnesses and conditions. CYP450 enzymes are most commonly found in liver cells. Within the cell, CYP450 enzymes can be found in the endoplasmic reticulum or in the mitochondria. There are approximately 60 CYP450 genes that have been identified in humans1. To make them easier to identify, each CYP450 gene has a name. That name consists of CYP, which tells you that it is a CYP450 gene, a family number, a subfamily letter, and another number that corresponds to a specific gene2. For example, CYP3A4, a common P450 gene, belongs to family number 3, subfamily A, and the gene number is 4. These genes are extremely important in the body, and understanding the genetic differences can be invaluable in personalizing medication regimens to better help each patient.

There are variations in the CYP450 gene caused by various polymorphisms1. A gene variation is indicated by an asterisk after the CYP450 gene name (e.g. CYP3A4*1)3. The *1 designation is given to what is considered the normal or “wild type” allele. Any other designation means that the individual has some variation in their gene code from what the wild type is (e.g. CYP3A4*4). Since there are two copies of each chromosome, we must take into consideration each of an individual’s two alleles for a given gene to determine the overall phenotype. A homozygous individual (two copies of the same allele) would have something listed like this: CYP3A4*1/CYP3A4*1. If an individual is heterozygous for a given CYP gene, they would have two different allele designations: CYP3A4*1/CYP3A4*4.

A person may have a genetic variant that causes them to be a fast metabolizer. This would mean that the drug is cleared quickly from the body4. Since it is metabolized quicker, the standard dose of a medication would not be useful, and person with this genetic difference may require a higher dose of the drug to have the same effect as a person with the standard CYP450 gene. A different type of genetic variation may cause a person to be a slower metabolizer. This means that they have a harder time clearing the drug as quickly4. A normal dose may cause unwanted toxic side effects. The side effects experienced would depend on the drug, and the severity could depend on the extent to which the metabolism is slowed. Either way, this can cause discomfort, and possible danger to a patient, and they would require a smaller dose than the average person to have the desired effect from their medication and avoid side effects. Understanding CYP450 enzymes and their effects on genetics can make it easier to find medications and doses that work the most effectively for each patient without making possibly dangerous guesses.

Not only can genetics affect the metabolism of medications, but medications can affect the enzymes produced from CYP450 genes. Medications can be categorized as CYP inducers, inhibitors, or substrates. A substrate would be a medication that is dependent upon the CYP450 enzymes for metabolism. An inducer would cause the CYP450 enzymes to metabolize substrates quicker than normal, causing them to last a shorter time in the body, and possibly produce a lesser effect4. In this case, the dose of the substrate may have to be increased if an inducer is added to the mix to make sure it still has the desired effect. An inhibitor would cause the CYP450 metabolism of a substrate to happen slower, and can cause the substrate to start giving the patient unwanted toxic side effects4. The dose of the substrate would have to be decreased for it to produce a desired effect and not cause toxic side effects. It is important to know the classification for certain drugs since they could cause an interaction with one another. This is another example of it being important for patients to know what drugs they are currently taking, because if a CYP inhibitor were added to a medication regimen that contained a CYP450 substrate, then there could be serious consequences for the patient if their doses were not properly adjusted.

Genes are important in determining the best drug regimen for a patient. Knowing how a patient metabolizes CYP450 metabolized drugs can personalize their medication regimen so it works the most effectively for them.

Sources of Information

1. US National Library of Medicine [Internet]. Bethesda (MD): US Department of Health and Human Services. Cytochrome p450; [updated 2017 Dec 19; cited 2018 Jan 5]; [about 1 screen]. Available from: https://ghr.nlm.nih.gov/primer/genefamily/cytochromep450

2. McDonnell AM, Dang CH. Basic Review of the Cytochrome P450 System. J Adv Pract Oncol. 2013 Jul; 4(4): 263-8.

3. Sim SC and Ingelman-Sundberg M. The Human Cytochrome P450 (CYP) Allele Nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Hum Genomics. 2010; 4(4): 278-81.

4. Manikandan P, Nagini S. Cytochrome P450 Structure, Function, and Clinical Significance: A Review. Curr Drug Targets. 2018; 19(1):38-54.