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Genetics and Pharmacology
Drug metabolism in humans is an essential topic to understand if one is to go into the pharmaceutical industry. When an individual ingests antibiotics their body is already prepared with the proper enzymes and molecular processes that allow for the breakdown and the uptake of these drugs. Xenobiotics encompass any substance that is foreign to the body; antibiotics fall into this category (Katzung, Masters, & Trevor, 2012). These are entities that the body does not produce naturally. Antibiotics are used for a variety of conditions, especially those that involve the infestation of bacteria in the human body. These bacteria could cause adverse reactions in humans that could result in illness, calling the need for antibiotics. However, after a drug in ingested, it is drug metabolism that takes over.
Drug metabolism is set up in a way that requires the liver to function properly in order to activate or de-activate certain parts of an antibiotic. A large portion of all xenobiotics must pass through the liver in order for the drug to have any effect on the body. This is known as first-pass metabolism (Katzung, Masters, & Trevor, 2012). This same first pass metabolism concept can also occur in the gastrointestinal tract. Once a drug is administered, most commonly orally, the drug is transported from the intestines to the liver through the hepatic portal circulation in order to go directly to the liver in order to become metabolized (Katzung, Masters, & Trevor, 2012). From there the metabolized portion of the drug goes into systemic circulation, and eventually to the target organ. This phase one metabolism is also known as oxidation/reduction, but it is through phase two metabolism that allows for conjugation/metabolism and encompasses the breaking down of the xenobiotic.
The drug that is ingested is either going to have a hydroxyl or an amine group added to it in order for it to become activated. The enzymes that become active during this time are the cytochrome P450 enzymes. The 450 stands for the 450nm peak in absorption that is witnessed after the heme proteins bind with carbon monoxide (Katzung, Masters, & Trevor, 2012). This enzyme system is in charge of 75% of all drug metabolism. A malfunction of any sort in this system can cause severe damage to the body's uptake of xenobiotics. The purpose of this system is to facilitate the transfer of the drug into the cells. Usually by the addition of R-groups to the proteins, the drug can more easily reach its destination. N-acetyltransferase (NAT) is an enzyme that is encoded by the NAT gene that adds an acetyl group to the drug in order to allow it to function (Meisel, 2002).
NATs in humans are essential for the correct metabolism and functioning of a drug. In order for a xenobiotic to become inactive, an acetyl group needs to be added (Meisel, 2002). The inactivation of a xenobiotic is done through an acetylation conjugation reaction; this process occurs separately from phase one. Compounds are added to the remnants of the drug that will make the drug more polar and more able to easily pass through to the target tissues. By catalyzing the conjugation process, drugs will be able to also be excreted more quickly and efficiently. N-acetyltransferase can be broken down into two separate enzymes NAT1 and NAT2.
NAT1 and NAT2 vary according to individuals. Some individuals may have an NAT1 and an NAT2 that may be faster or slower than those of another person (Boukouvala & Giannoulis, 2005). This has great effects on the drugs that require these enzymes in order for metabolism and excretion to occur. As aforementioned, the main priority of N-acetyltransferase is adding an acetyl group to enhance a drug's solubility. This is important in getting rid of the drug so that it may no longer affect the human body (Meisel, 2002). Both NAT1 and NAT2 genes are adjacent to one another and their effects are greatly induced by the genetic processes involved. Any deviation from the normal process can cause harm when intaking a drug. Polymorphisms found on these genes have given the pharmaceutical field another consideration when establishing and testing drugs (Boukouvala & Giannoulis, 2005). Any genetic variation may in fact induce a more sever situation if the mutation is unknown.
Polymorphic alleles have been identified on the NAT genes that lead to the different metabolism rates of xenobiotics. These polymorphisms vary from individual to individual and are the leading cause for the adverse reactions that are seen in drugs such as the anti-tuberculosis drug, or isoniazid. A polymorphic variation in NAT2 can cause a drug to react in different ways. First, this mutation can in fact speed up or slow down the process of metabolism and of acetylation in order to allow for the drug to work (Meisel, 2002). Because the acetylation in this case is most important when attempting to remove the drug from the body system, the time that it takes to go through this process is a very important one.
A polymorphism in the NAT gene can cause for slow acetylation. This means that the time that it takes for a drug to become inactivated and able to go through the cellular walls, and eventually excreted, is slowed down. This can cause serious effects if the process is slowed down too much and the drug stays active in the system for longer than it is supposed to (Boukouvala & Giannoulis, 2005). When this occurs, the blood has a severely high drug content, giving the xenobiotic more time to go into other neighboring cells and cause permanent damage. The drug begins to accumulate and continues to be activated because the rate of activation is faster than the rate of excretion. This overlap in the time that both of these processes take place gives ample time for the drug to cause permanent damage such as severe drug toxicity. If the drug stays in the systemic circulation for longer than it is supposed to, then it is actively killing off the foreign attackers in the human body, while simultaneously breaking down the human cells and the bacteria that is not meant to be killed off completely (Meisel, 2002). This in itself entails many more issues for the person, including the side effects seen in anti-tuberculosis drugs, due to the genetic mutations or polymorphisms of the NAT gene.
Any deviation in the normal genetic alleles of the NAT gene can not only cause a decrease in the acetylation process during drug metabolism, it can also cause fast acetylators to come into effect (Meisel, 2002). This means that the process is now quickened and can in fact make the drug ineffective if it is broken down and acetylated too quickly, making the excretion process of the drug even faster. If the xenobiotics are inactivated and excreted before they have time to actually do anything, then it is just the same as the individual not taking the drug to begin with. Antibiotics are made so that the active ingredients can have enough time to function and to get rid of any foreign invaders before the microorganisms have sufficient time to further attack the body (Meisel, 2002). In the case of tuberculosis, if not enough drug is administered, or if the polymorphisms in the NAT gene cause for fast acetylation, then the xenobiotic is quickly excreted with insufficient time to do any active work, allowing for the tuberculosis symptoms to take over and potentially cause permanent damage to the person.
There are numerous ways of detecting DNA polymorphisms. The most commonly used method is gel electrophoresis. This process allows for DNA to be inserted into an electrically charged gel and since DNA is negatively charged, the different sized alleles will move toward the positive end of the gel (Sapolsky & Lipshutz, 2003). The different molecules are seen according to size because the larger the fragments, the slower it will move, therefore the less it will travel. By comparing the DNA structures of the NAT gene, polymorphisms can be deduced. Another widely accepted way of detecting these polymorphisms is through the process of polymerase chain reaction or PCR. This process involves the amplification of very small fragments of DNA, allowing for the precise identification of certain loci (Sapolsky & Lipshutz, 2003). Being able to differentiate these structures with such high precision enables the identification of polymorphic genes.
The field of pharmacogenomics provides pharmacists with an immense amount of genetic information when it comes to the functioning of xenobiotics. By having this type of information available to them, they are most likely to give an effective dose to patients. Drugs are metabolized in the body in such a meticulous format, that any slight deviation from the normal processes can be fatal to people. The availability of genetic information can greatly reduce deaths and/or adverse side effects in antibiotics. Because of the limited information that has been available until now concerning genetics, drug doses are determined according to a generic scale. If the antibiotic is…[continue]
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