Acetaminophen

The second oxidative pathway involved in metabolising ethanol induced by individuals who chronically consume alcohol, is the microsomal ethanol oxidising system (MEOS), which involves a cytochrome P450, to be specific, the CYP2E1 isozyme, which is mainly present in the microsome and requires the electron carrier NADPH+ instead of NAD+ as for ADH (4). The induction of CYP2E1 by excessive alcohol consumption plays a vital role in metabolizing ethanol to acetaldehyde at elevated levels of ethanol concentrations (2, 3, 4). In addition to CYP2E1, inducing ethanol oxidation in the liver, CYP2E1¬ dependent ethanol oxidation may also occur in other tissues, such as the brain, where there is low levels of ADH activity. CYP2E1 also produces ROS, which increase the risk of tissue damage. Induction of the MEOS pathways, which involves CYP2E1, can lead to the production

Acetaminophen, once ingested into the body is rapidly absorbed from the gastrointestinal tract into the blood stream where it reaches peak plasma concentration in as little as half an hour. Here, it circulates around the body for a period of up to 4 hours during which it produces its analgesic and antipyretic effects before the acetaminophen is metabolised and deactivated by the liver by a possible 3 pathways: Glucuronidation, sulfation and oxidation (Show below in Figure 2). The most commonly used pathway is the glucuronidation metabolism, closely followed by the sulfation pathway. These methods of metabolism deactivate the acetaminophen in the hepatocytes into non-toxic conjugated sulphate and glucuronide which are excreted in the urine [23] [24]. The majority of the initially ingested therapeutic dosage is metabolised this way, with the remaining acetaminophen being metabolised via the third hepatic cytochrome P45 oxidase pathway, primarily by the enzyme CYP2E1 [25]. When acetaminophen is metabolised via this method, a small amount of a highly reactive toxic intermediate

Acetaminophen has been used for decades. In 1947 it was able to be bought by prescription only. Then in the 1960s it was then changed to be bought over the counter. It is one of the most commonly used analgesic-antipyretic medication for pediatrics and adults. The chemical name is N-acetyl-p-aminophenol (APAP). There is more than 200 over the counter medications, prescriptions that has acetaminophen listed as the primary drug. According to the American Association of Poison Control Center, acetaminophen is the most common pharmaceutical that has intentional and unintentional poisoning and toxicity. The most common of NSAIDs is aspirin (acetylsalicylic acid), it was put into modern medicine in 1899. Ibuprofen also known as Advil or Motrin, a

As a widely used analgesic and antipyretic agent, acetaminophen (APAP) overdose induced hepatotoxicity is one of the most common causes of acute liver failure in the USA and in most Western European countries [1]. Although a number of studies have forced on the influences of N-acetyl-p-benzoquinone imine (NAPQI), a highly reactive metabolite of APAP that depletes hepatic glutathione, and increases in oxidative stress during APAP toxicity [2], other mechanisms such as immune response also raise the susceptibility in the early stages of APAP-induced liver injury [3]. Accumulating evidence demonstrates a critical role of inflammatory cytokine released in early liver damage after APAP intoxication [4, 5]. Kupffer cells (KCs), the liver resident macrophages, are major sources of reactive oxygen species (ROS) and inflammatory

The periodic table has 118 elements. The compound we are going to focus on is acetaminophen. What is the drug acetaminophen? It is an over-the-counter drug that serves as a painkiller and a fever reducer. It is used to treat various conditions such as muscle aches, backache, toothaches, headaches, and arthritis. Although it is considered an analgesic because it is a pain reliever, it has no anti-inflammatory properties. Also, because it contains no anti-inflammatory properties, it is not a member of the non-steroidal anti-inflammatory drugs, also known as NSAIDs.

Aspirin a non-steroidal anti inflammatory drug(NSAIDs) with 3 main functions which are: analgesic, anti inflammatory, and antipyretic. NSAIDs is designed to inhibit the fatty acid COX enzyme which means that they also inhibit prostaglandins and thromboxanes. This enzyme is made up of COX 1 and COX 2. COX 1 is found in tissues and blood platelets which maintains homeostasis and produces prostaglandins. while COX 2 is responsible for the production of prostanoid mediators of inflammation. NSAIDs anti inflammatory effects are a result of COX 2 while their side effects are from inhibiting COX 1. Antipyretic action is a result of inhibition of prostaglandin production in the hypothalamus, the hypothalamus is what controls the balance between heat

Ibuprofen and Acetaminophen are synthetic mixes created to treat a collection of agony conditions. Ibuprofen can be utilized as a torment executioner and lessens irritation. The historical backdrop of ibuprofen can be followed back to 400BC times when Hippocrates utilized the willow leaf tea as a torment reliever for ladies amid labor. In 1763 Revererend Edward Stone uses willow bark to treat rheumatic fever. It wasn't until 1823 when the dynamic fixing, salicin, is separated from willow. The dynamic fixing was likewise found in 1838 by Swiss and German analysts in meadowsweet bloom. French researchers in 1853 makes salicylic corrosive from salicin. In any case, they understood an annoyed stomach is an unanticipated symptom of ingesting salicylic

The roles of antioxidants( Endogenous compounds) are to neutralize the excess of free radicals, to protect the cells against their toxic effects and to contribute in disease

These superoxides may be dangerous because they alter the structure of iron and protein via reduction. They may also undergo dismutation to form hydrogen peroxide which, in turn, gives rise to hydroxyl radicals, the most reactive ROS (Gulumian and Van Wyk, 1987; Agarwal et al., 2005). Hydrogen peroxide is not a free radical but its neutral charge allows it to pass through cell membranes and so this makes it very dangerous (Kurutas, 2015). Other internal or endogenous sources for these free radicals are inflammation, xanthine oxidase, peroxisomes, phagocytosis, exercise and ischaemia. Exogenous factors which lead to the development of these ROS include smoking, ozone, environmental pollutants, radiation, pesticides and drugs (Lobo et al.,

Based from observations made in the early 1950s, Denham Harman proposed that functional decline in cells and tissues was due to cumulative effects of macromolecular damage caused by oxygen radicals produced by respiratory enzymes (Harman 1956). This theory proposes that superoxide and other free radicals cause damage to the macromolecular components of the cell, resulting in accumulated damage to cause cells, and eventually organs, to stop functioning, leading to the aging phenotype (Sohal and Weindruch 1996, Clancy and Birdsall 2013). Oxidative damage is thought to occur from an imbalance when the antioxidant systems are unable to counter all the free radicals continuously generated during the life of the cell.

Reduction of an electron from ring C in ANT causes to formation of free radical semiquinone. This radical is partly stable in anoxic environment but under normoxic condition, its unpaired electron is given to oxygen and superoxide radicals are formed. Appropriate flavoproteins such as complex I catalyses reduced semiquinone radicals by accepting electrons from NADH or NADPH and delivering them to ANT. This sequence of reactions are known as “redox cycling” that can be very deterious (dangerous) because low amount of ANT is adequate for formation of many superoxide radicals (67). This radical damage triggers production of highly toxic aldehydes such as malondialdehyde (MAD). These aldehydes can diffuse easily in the cell and even from cell membrane

Although all in vitro models have limitations, our studies described in this thesis have demonstrated that these models, when used appropriately, will enable us to investigate specific research questions under different circumstances. By using different human-based in vitro models, our current findings have indicated that the high-dose APAP induces mitochondrial dysfunction, including the decrease in ATP synthesis and the increase in mitochondrial ROS formation, by disrupting the expression of key genes encoding the elements of respiratory chain complexes and mitochondrial and cellular specific antioxidants in both normal and inflamed livers (Chapter III and Chapter V). Besides, the whole-genome expression data obtained from PHH have suggested the high interindividual variation in the expression of genes participating in the Phase I/III drug metabolism/transport at baseline and the APAP-induced variation in genes involved in immune response may influence susceptibility to APAP hepatotoxicity (Chapter IV). The exposure of a 3D co-culture model to APAP with/without LPS has revealed the interaction between PHH and KCs (Chapter V). Through this novel model, we have identified that the median-dose APAP may reduce the KC phagocytic capacity by inhibiting the expression of Fcγ receptor-coding genes and prolong the clearance of pathogen and cell debris, which enhance KC mediated inflammatory response and exacerbate liver damage in

As you may know, antioxidants promote good health as they help avoid diseases. More specifically, antioxidants help slow down the oxidation of cells in our body. When cells oxidize, they generate free radicals, which are also known as cellular bi-products. It is perfectly safe to have a manageable amount of these free radicals in the body. However, when the free radicals are in excess, they can wreak havoc on our organism's cellular

The ability of p53 to regulate metabolism is also associated with the ability to regulate cellular ROS levels. As previously mentioned, p53 can either remove damaged cells that have suffered sustained oxidative stress, or limit levels of ROS in order to lower oxidative stress and consequently, potential cell damage. Through the regulation of carbohydrate and lipid metabolism, p53 is able to influence the response to ROS accordingly. By driving the expression of TIGAR and promoting PPP activity, p53 can increase the production of NAPDH, which can be used to generate the cellular antioxidant GSH (Bensaad 2006). Moreover, at the expense of nucleotide synthesis, p53 can also promote GSH synthesis following serine starvation, thereby lowering ROS

With all living organisms, a process known as cell respiration is integral in order to provide the body with an essential form of energy, adenosine triphosphate (ATP). Oxygen, although an essential part of this process, can form reactants from colliding with electrons associated with carrier molecules. (pb101.rcsb.org, 2017). Hydrogen peroxide is an integral product of this reaction but is known to impose negative effects on the body if high levels are introduced. Explicitly, this reaction is caused “If oxygen runs into (one of these) carrier molecules, the electron may be accidentally transferred to it. This converts oxygen into dangerous compounds such as superoxide radicals and hydrogen peroxide, which can attack the delicate sulphur atoms and metal ions in proteins.” (pdbh101.rcb.org, 2017). Research has suggested that the hydrogen peroxide can be converted into hydroxyl radicals, known to mutate DNA, which can potentially cause bodily harm due to DNA’s role in the synthesis of proteins. These radicals can cause detrimental effects on the human body, and studies have suggested a link to ageing. Due to the harmful effects of these H2o2, it is important that the body finds a way to dispose of hydrogen peroxide before concentrations are too great.