By A. Arakos. Magdalen College.
The chain reaction can be terminated by vitamin E and other lipid-soluble antioxidants that donate Nitroglycerin micardis 40mg on-line arterial doppler, in tablet form best micardis 80mg arrhythmia heart beats, is often given to patients with coronary artery dis- single electrons. Two subsequent reduction ease who experience ischemia-induced chest pain (angina). The nitroglycerin steps form a stable, oxidized antioxidant. This isoenzyme of nitric oxide synthase is regulated principally by induction of gene transcription, and not by changes in Ca2 concentration. It C N HN produces high and toxic levels of NO to assist in killing invading microorgan- isms. It is these very high levels of NO that are associated with generation of H2N N RNOS and NO toxicity. NO Toxicity •OH The toxic actions of NO can be divided into two categories: direct toxic effects resulting from binding to Fe-containing proteins, and indirect effects mediated by O compounds formed when NO combines with O2 or with superoxide to form RNOS. DIRECT TOXIC EFFECTS OF NO OH NO, as a radical, exerts direct toxic effects by combining with Fe-containing com- H2N N N H pounds that also have single electrons. Major destructive sites of attack include Fe- 8-hydroxyguanine S centers (e. Conversion of guanine to 8-hydrox- there is usually little damage because NO is present in low concentrations and Fe- yguanine by the hydroxy radical. The amount heme compounds are present in excess capacity. NO can cause serious damage, of 8-hydroxyguanosine present in cells can be however, through direct inhibition of respiration in cells that are already compro- used to estimate the amount of oxidative dam- mised through oxidative phosphorylation diseases or ischemia. The addition of the hydroxyl group to guanine allows it to mispair 2. RNOS TOXICITY with T residues, leading to the creation of a daughter molecule with an A-T base pair in When present in very high concentrations (e. Peroxynitrite, although not a free radical, is a strong Arginine Nitric oxide NO• O NO• synthase 2 NO• 2 NO2 N2O3 Nitric oxide Nitrogen trioxide Citrulline (free radical) (nitrosating agent) O– 2 NO• ONOO– NO– 2 Peroxynitrite Nitrite (strong oxidizing agent) physiologic H+ pH FORMS Diet, Arginine Intestinal OF HONO2 NADPH RNOS bacteria Peroxynitrous acid O2 NO synthase (Fe-Heme, NO NO – OH– •OH 3 FAD, FMN) Nitrate ion + Hydroxyl Nitric oxide (safe) + radical NADP+ NO2 + Smog Nitronium ion Citrulline NO2• Organic smoke (nitrating agent) Cigarettes Nitrogen dioxide Fig 24. Nitric oxide synthase synthesizes (free radical) the free radical NO. Like cytochrome P450 enzymes, NO synthase uses Fe-heme, FAD, Fig 24. The type of and FMN to transfer single electrons from damage caused by each RNOS is shown in parentheses. CHAPTER 24 / OXYGEN TOXICITY AND FREE RADICAL INJURY 447 oxidizing agent that is stable and directly toxic. It can diffuse through the cell and lipid membranes to interact with a wide range of targets, including protein methio- nine and -SH groups (e. It also breaks down to form additional RNOS, including the free radical nitrogen dioxide (NO2), an effective initiator of lipid peroxidation. Peroxynitrite products also nitrate aromatic rings, forming compounds such as nitrotyrosine or nitroguanosine. N2O3, which can be derived either from NO2 or nitrite, is the agent of nitrosative stress, and nitrosylates sulfhydryl and similarily reactive groups in the cell. Nitrosylation will usually interefere with the proper functioning of the protein or lipid that has NO2 is one of the toxic agents pres- been modified. Thus, RNOS can do as much oxidative and free radical damage as ent in smog, automobile exhaust, non–nitrogen-containing ROS, as well as nitrating and nitrosylating compounds. FORMATION OF FREE RADICALS DURING PHAGOCYTOSIS AND INFLAMMATION In response to infectious agents and other stimuli, phagocytic cells of the immune system (neutrophils, eosinophils, and monocytes/macrophages) exhibit a rapid con- sumption of O2 called the respiratory burst. The respiratory burst is a major source of superoxide, hydrogen peroxide, the hydroxyl radical, hypochlorous acid (HOCl), and RNOS. The generation of free radicals is part of the human antimicrobial defense system and is intended to destroy invading microorganisms, tumor cells, and other cells targeted for removal.
There are approximately 5 to 20 of these cells per 100 hepatocytes cheap micardis 40mg on-line blood pressure medication green capsule. The stellate cells are lipid-filled cells (the primary storage site for vitamin A) order micardis 80mg on-line hypertension specialist doctor. They also control the turnover of hepatic con- nective tissue and extracellular matrix and regulate the contractility of the sinusoids. When cirrhosis of the liver is present, the stellate cells are stimulated by various sig- nals to increase their synthesis of extracellular matrix material. This, in turn, dif- fusely infiltrates the liver, eventually interfering with the function of the hepatocytes. Pit Cells The CT scan of Amy Biasis’ upper abdomen showed an elevated right The hepatic pit cells, also known as liver-associated lymphocytes, are natural killer hemidiaphragm as well as several cells, which are a defense mechanism against the invasion of the liver by potentially cystic masses in her liver, the largest of toxic agents, such as tumor cells or viruses. Her clinical history as well as her history of possible exposure to various III. MAJOR FUNCTIONS OF THE LIVER parasites while working in a part of Belize, A. The Liver Is a Central Receiving and Recycling Center Central America, that is known to practice substandard sanitation, prompted her physi- for the Body cians to order a titer of serum antibodies The liver can carry out a multitude of biochemical reactions. This is necessary against the parasite Entamoeba histolytica because of its role in constantly monitoring, recycling, modifying, and distributing in addition to measuring serum antibodies all of the various compounds absorbed from the digestive tract and delivered to the against other invasive parasites. If any portion of an ingested compound is potentially useful to that organism, the liver will retrieve this portion and convert it to a substrate that can be used by hepatic and nonhepatic cells. At the same time, the liver removes many of the toxic compounds that are ingested or produced in the body and targets them for excretion in the urine or in the bile. As mentioned previously, the liver receives nutrient-rich blood from the enteric circulation through the portal vein; thus, all of the compounds that enter the blood from the digestive tract pass through the liver on their way to other tissues. The enterohepatic circulation allows the liver first access to nutrients to fulfill specific functions (such as the synthesis of blood coagulation proteins, heme, purines, and pyrimidines) and first access to ingested toxic compounds (such as ethanol) and to + such potentially harmful metabolic products (such as NH4 produced from bacter- ial metabolism in the gut). In addition to the blood supply from the portal vein, the liver receives oxygen- rich blood through the hepatic artery; this arterial blood mixes with the blood from the portal vein in the sinusoids. This unusual mixing process gives the liver access to various metabolites produced in the periphery and secreted into the peripheral circulation, such as glucose, individual amino acids, certain proteins, iron–trans- ferrin complexes, and waste metabolites as well as potential toxins produced dur- ing substrate metabolism. As mentioned, fenestrations in the endothelial cells, combined with gaps between the cells, the lack of a basement membrane between the endothelial cells and the hepatocytes, and low portal blood pressure (which results in slow blood flow) contribute to the efficient exchange of compounds between sinusoidal blood and the hepatocyte and clearance of unwanted com- pounds from the blood. Thus, large molecules targeted for processing, such as serum proteins and chylomicron remnants, can be removed by hepatocytes, degraded, and their components recycled. Similarly, newly synthesized molecules, such as very-low-density lipoprotein (VLDL) and serum proteins, can be easily secreted into the blood. In addition, the liver can convert all of the amino acids found in proteins into glucose, fatty acids, or ketone bodies. The secretion of VLDL by the liver not only delivers excess calories to adipose tissue for storage of fatty acids in triacylglycerol, but it also delivers phospholipids and cholesterol to tissues that are in need of these compounds for synthesis of cell walls as well as other functions. The secretion of glycoproteins by the liver is accomplished through the liver’s gluconeogenic capacity as well as its access to a variety of dietary sugars to form the oligosaccharide chains, as well as its access to dietary amino acids with which is synthesizes proteins. Thus, the liver has the capacity to carry out a large number of biosynthetic reactions. It has the biochemical where- withal to synthesize a myriad of compounds from a broad spectrum of precursors. At the same time, the liver metabolizes compounds into biochemically useful prod- ucts. Alternatively, it has the ability to degrade and excrete those compounds presented to it that cannot be further used by the body. These are accomplished by link- can be used to determine the normalcy of ing these agents covalently by way of biodegradable bonds to their specific carrier. These “tailor-made” pharmaceuti- recognition, uptake, transport, and biodegradation pathways. Inactivation and Detoxification of Xenobiotic receptor-related endocytic processes can be Compounds and Metabolites used as targets to probe specific receptor- Xenobiotics are compounds that have no nutrient value (cannot be used by the body mediated transport functions of the liver cells.