Chemotherapy and Drug Design (Essay Sample)

CHEMOTHERAPY AND DRUG DESIGN
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Chemotherapy and Drug Design
The Role of Iron in the Body and Its Homeostasis
The trace element, also referred to as micronutrient iron plays a significant role in some of the vital functions of the body. Iron is one of the numerous macromolecules within the human body that helps in the production of energy through the formation of adenosine triphosphate molecules, aiding in xenobiotic metabolism and facilitating ribonucleoside reductase activity in DNA synthesis (He et al, 2007; MacKenzie et al, 2007). The macromolecules consist of cytochromes, hemoglobin, flavoproteins, oxygenases and redoxins. As a result, iron becomes a vital part of the biological processes that take place in the human body. Iron, in its nature, is dichromatic; it can favorably participate in the production of energy by election transfer while it can also be toxic in electron transfer in the oxidation – reduction reactions. Cytoplasmic iron is usually in its reduced form and consequently it is always ready to undergo oxidation. As a result, in case the nearby lipids become peroxidized, DNA and other molecules may be damaged. This makes iron deficiency and severe iron overload to be equally dangerous and disastrous.
In mammalian tissues, the concentration of iron is not to be too high since it is usually sequestered by numerous host proteins such as lactoferrin and serum transferrin and as such it is usually not available. Hence, any microorganisms invading the body will compete with transferrin for the iron. Secreting sidorephores that usually bind with iron have the property of preventing any bacterial invasion into the body (Crossa and Payne, 2004). Any growth and multiplication of microorganisms are normally hindered by the presence of iron at the body’s physiological pH since its solubility is usually poor. An organism incapable of availing iron from its numerous sources will inevitably be unsuccessful as a pathogen. Gram negative microorganisms are usually recognized by the complexes of iron and siderophones at the specific outer membrane receptors. In the Gram positive organisms, it is the specific binding proteins that recognize the iron-siderophone complexes. Both the Gram positive and the Gram negative bacteria usually take iron from heme. The Gram negative bacteria use two methods. One is by binding to the outer membrane receptors and periplasmic binding of ABC permeases. The second one will involve the secretion of specialized bacteria protein sequesters from other sources. The proteins that act like siderophores are usually called hemophores. Hemophilus influenza has hemophore that capture that capture free heme from either the hemoglobin or the hemopexin. Pseudomonas organisms and Yersinia pestis have a second hemophore system (Crossa, 2004).
Immune functions, Erythropoiesis and oxidate metabolism are known to use iron (Munoz et al, 2009). Erythropoiesis basically refers to the production of red blood cells (RBCs). Through iron; a daily turnover of 1011RBCs in a normal adult is possible. In case of any damage as a result of either hemolysis or hemorrhage, the production of the RBCs will be rapidly stepped up by a quick response. Overproduction of the RBCs does not occur since erythropoiesis tends to be well regulated by the regulatory proteins which ensure that the RBCs circulating are within a normal range (Munoz et al, 2009, MacKenzie, 2007). In the first stage of the formation of the RBC, the stem cell normally changes into thyroid in the bone marrow. Consequently, the stages from the ethyroid to the orthochromatic erythroblast are usually influenced by erythropoietin. The orthochromatic erythroblast changes reticulocytes that circulate in the blood to become mature RBCs another day. Iron, vitamin B12 and folate are very essential for the differentiation and maturation of RBCs.
Oxidative Metabolism
Most metabolic processes normally require iron for proper functioning. However, excess iron in the body is harmful as it may cause damage to the body cells through oxidative stress occasioned by the release of free hydroxyl radicals which are usually very reactive and therefore harmful. The iron will therefore be absorbed but cannot be excreted and this will lead to accumulation of age which can be very lethal (He et al, 2007, MacKenzie et al, 2007).
A network of proteins has been related to iron metabolism. In most tissues, iron is usually bound to the transferrin receptor. Various enzymes involved in vital metabolic cycles require iron in their functioning; the citric acid cycle, succinate dehydrogenase and aconitase. Additionally, there are other enzymes that have iron incorporated as is the case with cytochrome oxidases and the iron - sulphur complexes of the electron transport chain. The iron- sulphur complexes are very essential in making adenosine triphosphate required for energy (He et al, 2007).Iron is required to facilitate the ribonucleoside reductase activity that takes place as a step of DNA synthesis. Iron is also required for myelogenesis and the maintenance of myelin within the central nervous system. Any disruptions of myelin can cause auditory defects among the children. Additionally, demyelinating diseases have also been associated with defective iron homeostasis. Neurotransmitters, noradrenaline, dopamine, serotonin need iron for as a co-factor in their synthesis. Parkinson’s disease and mood disorders have also been related to defective iron homeostasis (He et al, 2007).
Inflammatory-Stress Response
Iron and its homeostasis are very much linked to inflammatory responses. To combat the anemia of inflammatory illnesses, a tight control of homeostasis has to be in place (Wessling-Resnick, 2010). Hepcidin is the peptide hormone that controls iron homeostasis and as such its regulation will determine how the body iron homeostasis will occur. High iron stores have been proven to produce some susceptibility to disease and adverse responses to inflammatory infections and diseases (Wessling-Resnick, 2010). Physiological systemic mechanisms are therefore required to maintain a balance between nutrition and toxicity. Unlike other metals, iron through iron homeostasis is capable of controlling illnesses by using survival mechanisms.
Homeostasis
The total body iron requirement for a 70 kg male is 3.5 gm which is 50mg/kg body weight (Munoz et al, 2009). This iron is usually found within the hemoglobin of the RBCs making up 65% of the composition while 10% is composed in the myoglobin of muscle fibers. Enzymes and cytochromes hold just 350mg of iron while 200mg are stored in the liver, 500mg in the macrophages and 150mg within the bone marrow. Among the pre- menopausal women, their total body iron tends to be less. Normal diet contributes 15-20mg of iron whose absorption is 1-2mg/day. The body’s level of iron is mainly controlled by activities such as menstruation, sloughing of intestinal mucosal cells and other minor blood losses. Erythropoiesis requires an internal turnover of 20-30mg/day of iron while there are no research findings confirming the excretion of iron (Munoz et al, 2009). Iron homeostasis is depends heavily on daily consumption from the duodenum which is very essential for the oxidative metabolism of the cells. However, excessive iron is usually highly toxic to the cells and causes cell death by free radical formation with lipid peroxidation (Munoz et al, 2009). Consequently, to achieve better results, iron homeostasis must be properly regulated. Cellular iron is usually regulated by some proteins from the non heme tissues to ensure that the iron is optimally in the body.
The body’s primary needs for iron are recycled by the reticulo-endothelial system from the remains of the RBCs (Wessling-Resnick, 2010). For a normal person, iron conserved in the stores is usually sufficient for the body. However, in cases of pregnancy, bleeding illness, loss of blood in trauma and hypoxia additional requirement is usually essential. These are the situations that determine the body’s total iron requirement. The process of availing iron in the body is normally streamlined by the duodenal enterocytes. Hereditary haemachromatosis upsets iron management system allowing excess iron to enter the body and thus overloading it. In cases such as anemia of inflammation or chronic illnesses, iron absorption will become limited and will be retained in the reticulo-endothelial system thus distorting the natural flow of events (Wessling-Resnick, 2010).
Several proteins participate in iron homeostasis during the absorption process (Munoz et al, 2009). Regulating these proteins is very important in maintaining iron homeostasis since it is the absorbed iron that ultimately decides the iron content within the body (Wallander, 2006). Normal diets contain heme and non-heme iron. The heme iron is usually obtained from meat and is easily digested. Its digestion is supported by the pancreatic enzymes within the intestines (Johnson-Wimbley and Graham, 2011). The globin moiety is separated from the helm. On the other hand, non-heme iron is usually obtained from cereals, beans and vegetables but its absorption is comparably less and it is either in the ferric (Fe+2) or ferrous state (Fe+3).
The acidic pH of the stomach enhances the Bioavailability of dietary iron (Johnson-Wimbley and Graham, 2011). In the presence of Vitamin C, precipitation of ferric iron is prevented. Before absorption, ferric iron, if present, must be converted into the ferrous state by the duodenal cytochrome b. Absorption of non-heme iron is reduced by grains and non-herbal tea. The transfer of iron in heme and non-heme is in form of ferrous iron across the intestinal mucosa into the enterocyte in absorption. This occurs through export of ferroprotein and oxidation by hephaestin or ceruloplasmin (Wessling-Resnick, ...