Amplichip?
Related Terms
Amplichip?, cytochrome P450, CYP1A2*1F gene, CYP2D6 gene, CYP2D6 protein, CYP450 gene, CYP450 protein, caffeine, drug metabolism, genotype, molecular testing, PCR, pharmacodynamics, pharmacogenomics, pharmacokinetics, polymerase chain reaction, real time polymerase chain reaction, real time PCR, RT-PCR.
Background
The term "metabolism" refers to the way the human body interacts with drugs, food, and any other ingested substance. Metabolism involves absorption in the digestive tract, processing in the liver and other organs, action of the substance within the cells, and elimination in the urine or stool. Pharmacokinetics is the study of how a drug is absorbed, processed, delivered to its target, and removed from the body. Pharmacodynamics is the study of how a drug interacts with its target. This target may be a protein within the cell, genetic material within the cell, or something outside of the cell.
Genes are molecules within the cells that provide instructions for making all of the proteins in the body. While about 99.9% of genetic material is the same among individuals, each individual has slightly different genes, called alleles. Different alleles may produce proteins that have stronger or weaker levels of activity compared with other alleles.
Pharmacogenomics is the study of how an individual's genetic makeup affects his or her response to drugs. Some patients respond differently to drugs from others. For instance, one patient may require a very high dose of a certain medication to have an effect, while another patient may have major side effects from a small dose. Pharmacogenomics includes the study of both pharmacokinetics and pharmacodynamics.
Drug and nutrient metabolism: The metabolism of drugs and nutrients occurs primarily in the liver. One family of proteins, called cytochrome P450, is responsible for metabolizing most drugs. When these proteins metabolize drugs, they break them down into different molecules or attach them to other proteins. In most cases, this results in the drug being inactivated.
There are more than 60 different types of cytochrome P450 proteins, but six of them are responsible for metabolizing 90% of the drugs used today. One of these proteins, CYP2D6, is responsible for the metabolism of 25% of all drugs. CYP2D6 metabolizes many drugs used to treat high blood pressure, irregular heartbeats, depression, pain, and psychosis. Another cytochrome P450 protein, CYP1A2, metabolizes caffeine and, to a lesser extent, drugs.
Some alleles provide instructions for making cytochrome P450 proteins that do not work as rapidly as others. Patients with these alleles produce proteins that metabolize certain drugs more slowly because the drugs and nutrients are removed from the body more slowly and are present at higher levels in the blood for longer periods of time.
CYP2D6: There are more than 60 different alleles of the CYP2D6 gene. Some of these have no effect, while others provide instructions for making proteins that do not work at all. Some alleles provide instructions for making proteins with a decreased level of action, resulting in slower metabolism and higher levels of certain drugs circulating in the blood. About 10% of Caucasians have an allele that produces a protein that causes them to metabolize certain drugs more slowly. These alleles occur in about 10% to 20% of people of African descent and about 5% of Asian individuals.
Some people have extra copies of the CYP2D6 gene. This results in the production of extra proteins that more rapidly metabolize certain drugs, potentially decreasing the levels of the drug in the blood and thereby the effect of the drug.
CYP1A2: The CYP1A2 protein metabolizes drugs, the hormone estrogen, and caffeine. Smoking and consumption of cruciferous vegetables (such as broccoli) and charcoal-grilled meat increase the activity of the CYP1A2 gene, and thus the levels of the CYP1A2 protein in the liver. One allele, called CYP1A2*1F, provides instructions for making a protein with much less activity than others. The frequency of this allele in different ethnic groups is uncertain.
The decreased activity of the protein produced by CYP1A2*1F causes people with this allele have higher caffeine levels in the blood when they drink caffeinated beverages. This allele is also linked to a higher rate of precancerous growths in the colon and increased susceptibility to the harmful effects of smoking, such as emphysema and lung cancer.
Methods
Polymerase chain reaction: Polymerase chain reaction (PCR) is a method of multiplying a small piece of DNA millions of times in order to study it. To perform PCR, cells are collected from a patient's blood or cells from the inside of the mouth. A probe, or sequence of DNA that recognizes the allele of interest, is added to the patient's DNA. After the probe attaches to the allele, proteins are added that make millions of copies of the gene. This allows researchers to determine whether a specific allele is present.
For example, a sample of blood from a patient can be tested by PCR to detect the CYP2D6 alleles that are associated with slower metabolism of drugs. PCR can also be used to detect the CYP1A2*1F allele that makes patients more sensitive to caffeine.
PCR results can identify the presence and amount of the specific allele. Any person may have one or two copies of an allele, and PCR can provide this information. Two copies of an allele with abnormal activity will have a greater effect than one copy of an abnormal allele. Real time PCR is a special PCR method that can determine how much of an allele is present.
Research
Currently, the U.S. Food and Drug Administration (FDA) has approved a lab test that detects the most common variant alleles of the CYP2D6 gene. This test, called Amplichip?, is available from specialized labs.
Amplichip? detects common allele variants in two different enzymes involved in drug metabolism, CYP2D6 and CY2C19. Segments of DNA called probes are used to detect the presence of allele variants. Each probe attaches to a specific allele and causes a fluorescent glow if it is present. The allele variants detected with Amplichip? allow doctors to determine whether a patient metabolizes drugs more quickly or slowly than the average person.
Researchers are currently looking at the use of Amplichip? and other methods of detecting CYP2D6 variants to determine when and how this information is most useful. Many drugs used by psychiatrists are metabolized by the CYP2D6 protein so these physicians may be the first to use this test on patients. Research is also being conducted to determine the effect of CYP2D6 allele variants on some medications for irregular heartbeats, high blood pressure, and pain. The presence of some CYP2D6 variants may increase the risk of dementia, but this has not been proven. Research is under way to confirm this.
Previous research has linked the CYP1A2*1F allele to an increased risk of some types of cancer. Ongoing research seeks to confirm this and determine its significance. In addition, research is examining the effect of this allele in combination with cigarette smoking.
Implications
The ability to detect allele variants in the CYP450 genes will help doctors determine which patients are at risk for severe side effects and which patients may not benefit at all. Patients with alleles that cause them to metabolize certain drugs more slowly are more likely to develop side effects from drugs that are broken down by the cytochrome P450 proteins. Doctors can use this information to adjust the dosages of medication or to choose a different medicine.
Preliminary research has shown the CYP1A2*1F allele to be a risk factor for some types of cancer, such as colon and breast cancer. More research is needed to clarify this. If this allele is shown to be linked to cancer, testing for it may help doctors determine how early and frequently to screen certain patients for cancer.
Limitations
The consequences of abnormal alleles in the CYP450 genes is not well understood. To determine exactly what the presence of these alleles means for patients, large clinical trials are needed.
Future research
In the future, examination of these genes may be combined with the examination of completely different genes to determine a larger pattern of genetic activity. For instance, variants in genes that are responsible for the delivery of drugs from the blood to the tissue, and genes that interact with drugs in the cell, may also affect how an individual responds to a specific drug.
By combining the information from CYP450 genes with information from other genes, it may become possible for more personalized medicine to be prescribed. Theoretically, this could prevent side effects and allow doctors to use the best drugs for each individual. New alleles in the CYP450 genes are still being discovered, and how these new alleles affect an individual's metabolism is currently unclear.
Author information
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
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