Arylamine N-acetyltransferase is a protein involved in the metabolism of many different molecules that enter the body. The genes NAT1 and NAT2 provide instructions for making the two main arylamine N-acetyltransferases, called NAT1 and NAT2. Both these proteins metabolize some molecules to make them more or less active within the body. Some of the molecules metabolized by NAT1 or NAT2 include drugs, such as the antibiotic isoniazid, and substances in the environment that may cause cancer, such as cigarette smoke.
Metabolism refers to the way in which 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.
Genes provide the instructions for making proteins, which perform metabolic functions in the body. Genes are found inside the nucleus of the cells of all organisms. An individual's genes are contained in a large molecule called DNA (deoxyribonucleic acid), which looks like a twisted ladder. This unique shape is called a double helix. The sides of the double helix are made of alternating sugar and phosphate molecules. The "rungs" of the "ladder" are made of small molecules called bases. These molecules include adenine, thymine, cytosine, and guanine. The pattern of these four molecules in a gene determines which protein is produced.
DNA differs slightly from individual to individual. If these differences are present in a gene, they are called alleles or polymorphisms. Differences in alleles may result in genes that code for proteins with more or less activity than others. Differences in parts of the DNA that do not code for proteins may affect whether or not a gene is active. For instance, one person may have a small difference in a part of their DNA that causes a nearby gene to become inactive. This person would therefore not have the protein created by that inactive gene.
Gene variations, called polymorphisms, exist in both the NAT1 and NAT2 genes. This means that people have differences in these genes that cause them to produce more or less NAT1 or NAT2 protein than another person. Someone who produces more NAT1 or NAT2 protein would metabolize substances more rapidly, whereas someone who produces less NAT1 or NAT2 protein would metabolize substances more slowly. An individual can have polymorphisms in one or both of these genes.
There are many different polymorphisms for the NAT1 and NAT2 genes, many of which have not yet been identified. How each of these polymorphisms affects the gene is also unknown. What is clear is that some polymorphisms cause more protein to be produced, which results in faster metabolism, while others cause less protein to be produced, which results in slower metabolism.
What these differences mean is still uncertain and is currently the subject of much research. Some experimental studies have shown that polymorphisms in the NAT1 and NAT2 genes are associated with increased risk of cancer, birth defects, and side effects from some drugs. Types of cancer that may be associated with the NAT 1 and NAT 2 gene polymorphisms include colon, liver, and breast cancers. How these polymorphisms lead to cancer is unknown, but it may be related to an inability to remove environmental toxins from the body. The exact relationship between these gene polymorphisms and cancer is still uncertain. Drugs that may be affected by these polymorphisms include the antibiotic isoniazid and the blood pressure drug hydralazine. While an increased risk of birth defects and drug side effects has been found to occur with some polymorphisms, this has not yet been proved.
Pharmacogenomics is the study of how an individual's genetic makeup affects his or her response to drugs. Some patients respond differently to drugs than 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. Pharmacokinetics is the study of how a drug is metabolized in 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.
Polymerase chain reaction (PCR): Polymorphisms in the NAT1 or NAT2 genes are detected by polymerase chain reaction (PCR). PCR is the most commonly used method for pharmacogenomic testing. A small sample of cells is taken from a tumor that has been surgically removed, from a blood sample, or from a swab of the inside of the mouth. The genetic material is copied hundreds of times to create a larger sample. Molecules called "probes," which are DNA segments specifically designed to attach to a specific allele, are then used to tag the gene and identify it. Probes can be used to identify gene variants and to determine the amount of variant gene that is present.
PCR can be used to detect variations in the NAT1 and NAT2 genes that process and inactivate drugs and environmental toxins. If a gene variant is identified in a patient, this may mean that the patient has an increased risk of side effects from drugs or toxins that interact with the NAT1 or NAT2 protein. Based on this knowledge, doctors may choose to prescribe different drugs, or different doses, to these patients. Doctors may also choose to screen these patients at an earlier age for the effects of environmental toxins, such as cancer.
DNA sequencing: DNA sequencing is a method of determining the exact pattern of adenine, guanine, cytosine, and thymine in a DNA fragment. These four molecules determine which protein is produced and how much is made. A gene with a slightly different pattern of these molecules will produce a slightly different protein or may produce more or less of the protein. An individual with a different pattern of these molecules may therefore have more or less active NAT1 or NAT2 proteins.
DNA sequencing is used in research to study a new polymorphism and to determine its exact structure. By knowing the structure of a specific polymorphism, researchers may be able to determine what effect it has in the body. To sequence DNA, the DNA molecule is first heated and mixed with a small piece of genetic material, called a primer, which attaches to a specific point on the DNA. Once the primer is attached, a protein called DNA polymerase is signaled by the primer to make a copy of the DNA. DNA polymerase uses nucleotide bases to create copies of the DNA. Some of the nucleotide bases that are used to create the DNA copies act as signals to stop creating a new molecule. These "stop" signals will be incorporated randomly throughout the new DNA copies, and they give off a visual signal, such as fluorescent light or a color. Thus, after millions of copies have been made, the nucleotide bases with a fluorescent or color signal can be detected, and then the nucleotide base at that position is known. This process is repeated until all of the nucleotide bases have been identified.
Cancer: Research is currently focusing on understanding the importance of NAT1 and NAT2 gene variants in human health. While some studies have shown that certain polymorphisms are linked to cancer, others have not. Further research is being performed to clarify the relationship between NAT1 and NAT2 gene variants and cancer and to determine exactly which variants are associated with an increased risk. Epidemiologic studies seek to determine whether specific ethnic groups have the NAT1 and NAT2 gene variants, and whether people who have these variants react differently to drugs or develop cancer at higher rates than those who don't.
Drug metabolism: Researchers are also working to determine exactly which drugs are metabolized by the NAT1 and NAT2 proteins and how the polymorphisms in their respective genes affect drug metabolism. By determining which drugs interact with these proteins, doctors may one day be able to test for genetic variants in the NAT1 and NAT2 alleles that will determine how a person will react to a certain drug. Based on this information, patients with NAT1 or NAT2 gene variants may be treated with different medications or with different doses of medications than patients with a different gene allele.
In the future, testing for NAT1 and NAT2 gene polymorphisms may be done to determine a person's risk of cancer or to determine how their body will react to some drugs.
If a patient is found to have a polymorphism linked to an increased risk of cancer, a doctor might decide to monitor the person more closely and to perform screening tests at an earlier than normal age and at regular intervals to detect any potential cancer early.
If a patient is found to have a polymorphism that puts him or her at risk for severe side effects of a specific drug, a doctor may choose to use a lower dose or a different drug to avoid these side effects.
NAT1 and NAT2 genetic testing is still in the research stage, and it will probably be several years before these tests become available to the public. A significant amount of research will be required before testing for polymorphisms in the NAT1 and NAT2 genes is shown to be useful. The ability of doctors to use NAT1 and NAT2 genetic testing is also limited by a lack of data regarding the implication of genetic variants.
Future research will continue to focus on identifying the polymorphisms of the NAT1 and NAT2 genes. In addition, determining the effects of these polymorphisms on human health is also an area for future research. Research may be conducted to determine the effect of NAT1 and NAT2 gene variants on the development of many different kinds of cancer, on the aging process, and on the development of dementia.
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The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.