Damage Caused by Chemical Agents PDF

DAMAGE CAUSED BY CHEMICAL AGENTS  Mechanisms of action of chemical agents - Direct damage: e.g. cyanide, mercury chloride, antineoplastic chemotherapeutics, amanitins - Indirect damage: not caused by the substance as such but by a derivative of the substance, which is produced by the body i...

DAMAGE CAUSED BY CHEMICAL AGENTS  Mechanisms of action of chemical agents - Direct damage: e.g. cyanide, mercury chloride, antineoplastic chemotherapeutics, amanitins - Indirect damage: not caused by the substance as such but by a derivative of the substance, which is produced by the body itself: Damage can result from: An intermediate that is toxic From free radicals that are produced during the biotransformation process of the substance Chemical entry routes  ABSORPTION AND DISTRIBUTION TOXIC SUBSTANCES If not immediately excreted by the kidneys (in the Lipid carriers Water soluble case of water-soluble substances), hydrophobic WATER- substances are metabolized, often through different SOLUBLE enzymatic pathways with the formation of: SUBSTANCES products that may be more or less toxic than the ARE LESS TOXIC starting substance; THAN conjugated products that are more soluble and HYDROPHOBIC therefore easily eliminated. SUBSTANCES Toxic products can interact with a target molecule causing damage The site of toxicological damage is often where the transformation of toxic metabolites takes place Both phases require cofactors (=Nutrients Needed) THE LIVER IS THE MAIN SITE OF THE ENZYMATIC TRANSFORMATIONS OF EXOGENOUS SUBSTANCES (Xenobiotics) The P450 system is located in the liver at the level of the smooth endoplasmic reticulum (microsomes) and in the mitochondria. Its activity is also present in the skin, eyes, lungs, gastrointestinal mucosa, kidneys and brain  Phase I Metabolism: Cytochrome P450 Cytochrome P450 (CYP) enzymes are the most important in biotransformation in terms of catalytic versatility and number of xenobiotics it metabolizes: 57 isoforms have been identified in humans CYP (gene family)(subfamily)(individual gene) CYP1A2: metabolizes caffeine CYP3A4: most abundant CYP with broad substrate- specificity CYP2E1: metabolizes acetaminophen and ethanol Most CYPs are localized in the liver at the level of the smooth endoplasmic reticulum. CYPs are proteins containing a heme group. ER and mitochondrial CYPs play a key role in the biosynthesis or catabolism of steroid hormones, bile acids, fat-soluble vitamins, fatty acids, and eicosanoids. This system is inducible and this is the basis of drug tolerance and addiction. It is also responsible for the transformation of xenobiotic substances into reactive intermediate products or terminal carcinogens.  CYP ENZYMES HAVE BEEN IDENTIFIED IN ANIMALS, PLANTS, FUNGI, BACTERIA, AND EVEN VIRUSES. MORE THAN 50000 DIFFERENT CYP  Xenobiotics metabolized by cytochrome P450 Reaction Examples Hydroxylation comp. aliphatics Valproic acid, pentobarbital Hydroxylation of aromatic comp. Benzopyrene, phenobarbital Epoxide formation Benzene, benzopyrene Oxidative dealkylations Phenacetin, morphine, caffeine Oxidative deamination Amphetamine Oxidation of N or S or P Chloropromazine, acetaminophen Halogen removal Halothane Oxidation of alcohols Ethanol Reduction (low [O2]) Alothane, CCl4 Alcuni substrati dei CYP450 Grapefruit juice can block the action of intestinal CYP3A4, so instead of being metabolized, more of the drug enters the bloodstream and stays longer in the body. The result: too much drug in circulation. CYTOCHROME P450-DEPENDENT MONOOXYGENASE SYSTEM Membrane-bound monooxygenase complex of liver. R – NAD(P)H-cytochrome P450-reductase (donor of reducing equivalents, contains FAD); b5– cytochrome b5 (intermediate electron carrier); P450 – cytochrome P450 (terminal component of the system – electron acceptor); XH – nonpolar substrate. ETHANOL METABOLISM The main metabolic mechanism of ethanol is oxidation by dehydrogenase enzymes of the stomach and liver: 1) Alcohol dehydrogenase (ADH, present in the cytosol): converts ethanol into acetaldehyde; 2) Aldehyde dehydrogenase (ALDH, present in the mitochondria): which converts acetaldehyde into acetate. STOMACH ADH is found in the cells on the surface of the mucosa of the entire gastrointestinal tract, with highest concentration in the gastric mucosa it constitutes a first barrier to the absorption of this substance, it reduces the amount of alcohol that reaches the intestine and from here penetrates the systemic circulation. ADH is present in a significantly different concentration between men and women; For this reason, women cannot consume the same amounts of alcohol as men, but about 50% less, as they have an enzymatic activity equal to about half that of men. ETHANOL METABOLISM in the stomach and liver Since O2 is used in this reaction and there is an liver e-transfer, ROS can be (MEOS) generated mucosa Gastric and liver liver CYP2E1: Cytochrome p450, family 2, subgroup E1 MEOS: Microsomal Ethanol Oxidation System ADH: alcohol dehydrogenase; ALDH: aldehyde dehydrogenase What is the Alcohol Unit Alcohol consumption is measured in units of alcohol. The alcohol unit corresponds to 12 grams of ethanol, contained in a can of beer (330 ml), a glass of wine (125 ml) or a small glass of liqueur (40 ml), at the typical strengths of these drinks.  In the liver of the occasional/moderate drinker, most ethanol is 1 metabolized by the ADH/ALDH pathway Thanks to the enzyme Acetyl-CoA synthetase, ACETATE is bound to CoA to form acetyl-CoA. This can then be started : -to the Krebs cycle, but this is slowed down if there is NAD deficiency. -the biosynthesis of fatty acids and their accumulation as triglycerides.  If the cytosolic ratio NADH/NAD increases, lipid biosynthesis is stimulated. NAD is essential for dehydrogenases that play a critical role in cellular metabolic processes, such as glycolysis, the Krebs cycle, and β-oxidation. Excess NADH prevents these processes. Fat accumulation (lipidosis) occurs even after taking relatively low doses 2 In the liver of the chronic alcohol user, most ethanol is metabolized by the MEOS pathway The system is represented by microsomal enzymes, or MEOS. The main enzyme involved is CYP2E1 which uses NADPH as an electron donor and O2 as an acceptor. It can generate large amounts of oxidizing species (O2−, H2O2) MEOS is an inducible system, so the number of enzymes increases in case of increased stimulation. The intake of ethanol leads to alterations in drug metabolism (e.g. paracetamol) substrates of CYP2E1. Also through this pathway, NADH increases to the detriment of NAD, because acetaldehyde is produced which is converted into acetic acid, but the main problem that occurs when this pathway prevails over that of ADH, is the production of ROS.  3 metabolic system of alcohol, which, however, participates to only minimal part in both conditions is represented by a catalase that catalyzes The following reaction: CH3CH2OH + H2O2 => CH3CHO + H2O Ethanol acetaldehyde acetate The rate of formation of acetaldehyde is higher than that of its catabolism, so in excess of alcohol, the liver is unable to convert all the acetaldehyde into acetate, and pours it into the circulation. Most acetaldehyde damage occurs in the liver, but its toxicity to the heart and central nervous system has also been demonstrated: -Impairs cardiac contractile function. -In the brain, it increases levels of the inhibitory neurotransmitter GABA (gamma-amino-butyric acid), also known as the "inhibitor" neurotransmitter. In fact, it reduces neuronal excitability leading to a "slowing down" of electrical impulses.  Ethanol, and its derivative acetaldehyde, have a biphasic effect on the human body. Initially, it can induce a state of euphoria and disinhibition, due to its ability to increase the release of dopamine in the brain However, as the amount consumed increases, the depressant effects of alcohol take over. Alcohol inhibits the functioning of the central nervous system, slowing down cognitive and motor functions. This can lead to reduced judgment, coordination problems, and in extreme cases, unconsciousness or coma.  DANNI DA ACETALDEIDE NEL FEGATO Forms adducts with DNA forms adducts with lipids (altering the lipid composition of membranes damage to biological membranes (probably due to the formation of adducts with lipids and proteins) and this causes: at the level of the RER membranes, decrease in protein synthesis; at the level of mitochondrial membranes, decreased production of ATP acetaldehyde binds to tubulin, impairing the function of microtubules, which leads to a reduction in the transport of lipoproteins of hepatic origin and consequent blocking of the release of VLDL into the circulation. The formation of protein adducts by acetaldehyde leads to the formation of neoantigens on the surface of the hepatocyte responsible for immune- mediated damage to the hepatocytes that persists even if alcohol intake is stopped.  Danno alle membrane mitocondriali lo causano (oltre all’acetaldeide) anche i ROS che derivano dall’ossidazione dell’alcol ad opera di MEOS ROS produced through the MEOS pathway peroxidize lipids, thereby altering the impermeability of the mitochondrial membrane. Proper impermeability of the mitochondrial inner membrane is instrumental in maintaining the proton gradient between the matrix and the inter-membrane space, a gradient necessary for ATP production by ATP synthetase. If the permeability increases due to lipid peroxidation, the gradient is lost and ATP-synthetase cannot function. ATP deficiency impacts all cellular processes, including the ability of cells to maintain osmotic balances through membrane pumps. Hepatocytes die from the energy crisis. Fatty acid metabolism Fatty acid metabolism in the normal liver in the alcoholic's liver AGs arrive in the liver bound to albumin Blockade of b-oxidation (due to excess and lipoproteins. NADH and damage to mitochondrial In the liver, they are released and: membranes by acetaldehyde and ROS). 1) undergo the process of b-oxidation; Blockade of apo-lipoprotein synthesis 2) they are esterified into (due to excess acetaldehyde and ROS phospholipids; damaging the RER). 3) they are conjugated with cholesterol Increased biosynthesis of fatty acids to form cholesterol esters (storage (Acetyl-CoA is not used in the Krebs molecules); cycle because NAD is lacking). 4) they form triglycerides and are Increased incorporation into inserted into lipoproteins-VLDL-which triglycerides. transport fatty acids to peripheral Triglycerides accumulate because tissues; If they are not used, they lipoproteins are not formed and accumulate in adipose tissue. secreted. STEATOSIS OR FAT DEGENERATION IN CHRONIC ALCOHOL INTAKE ABNORMAL ACCUMULATION OF TRIGLYCERIDES IN LIVER CELLS LIVER, mainly involved in the metabolism of fatty acids. Frequent steatosis in the liver but also in the heart, muscles and kidneys. FEGATO STEATOSICO FEGATO NORMALE Hepatic steatosis is a reversible degeneration of cells, problem when it becomes chronic Massive death from liver cell necrosis Alcoholic liver disease Release of DAMPs with activation of inflammation Irreversible liver damage: CIRRHOSIS Subversion of the lobular architecture of the liver due to a fibrotic process that affects the entire organ (scarring process). Hepatocytes are gradually replaced by fibroblasts and extracellular matrix: the functional tissue is replaced by a tissue that does not perform hepatic functions: maintenance of the architecture of the organ but not of its function. Regenerative nodules (which can develop into carcinoma) may develop.  Steatosis occurs whenever fat disposal pathways are inhibited: catabolism, lipoprotein supplementation, phospholipid synthesis a) The β-ox of fatty acids, which is completed by the Krebs cycle, occurs in the mitochondria. Any damage to mitochondrial physiology brings with it steatosis. Including damage from ROS. b) Poor or no-intake of proteins and aa as in insufficient nutrition (from hunger, from high alcoholism that generates loss of appetite, from unbalanced diets). This is because it decreases the synthesis of apo-lipoproteins that serve to assemble the lipoproteins that carry lipids out of the liver. In addition, the synthesis of phospholipids is lacking: methionine is used for the synthesis of S-adenosyl methionine which serves as a methyl donor in the synthesis of phospholipids (phosphatidylcholine). c) Inhibition of protein synthesis due to the action of certain toxins (ricin, diphtheria toxin)