Lecture 2 Chemistry Of Toxicology PDF

CHEMISTRY OF TOXICOLOGY CH523 HANAA KHALIL ASHOUR LECTURE 2  III- Metabolism The biochemical changes that substances undergo in a living organism are called metabolism. Metabolism describes the catabolic reactions by which chemical species are broken down...

CHEMISTRY OF TOXICOLOGY CH523 HANAA KHALIL ASHOUR LECTURE 2  III- Metabolism The biochemical changes that substances undergo in a living organism are called metabolism. Metabolism describes the catabolic reactions by which chemical species are broken down by enzymatic action in an organism to produce energy and components for the synthesis of biomolecules required for life processes. It also describes the anabolic reactions in which energy is used to assemble small molecules into larger biomolecules. Metabolism is an essential process for any organism because it provides the two things essential for life —Energy and Raw materials. Metabolism is important in Toxicological Chemistry for : (1) Interference with metabolism is a major mode of toxic action. (2) Toxic substances are transformed by metabolic processes to other materials that are usually, though not invariably, less toxic and more readily eliminated from the organism.  it is important to keep in mind the pathways of nutrients and xenobiotic in organisms. For humans and other vertebrate animals, materials enter into the gastrointestinal tract , in which substances are broken down and absorbed into the bloodstream. Most substances enter the bloodstream through III- METABOLISM the intestinal walls and are transported first to the liver, which is the main organ for metabolic processes in the human body. The other raw material essential for metabolic processes, oxygen from air, enters blood through the lungs  Biotransformation: Refers to changes in xenobiotic compounds as a result of enzyme action. Reactions not mediated by enzymes may also be important. As examples of no enzymatic transformations, some xenobiotic compounds bond with endogenous biochemical species without an enzyme catalyst, undergo hydrolysis in body fluid media, or undergo oxidation–reduction processes. The likelihood that a xenobiotic species will undergo enzymatic metabolism in the body depends on the chemical nature of the species. Compounds with a high degree of polarity, such as relatively ionizable carboxylic acids, are less likely to enter the body system and, when they do, tend to be quickly excreted. Therefore, such compounds are unavailable, or available for only a short time.  for enzymatic metabolism.Volatile compounds, such as dichloromethane or diethyl ether, are expelled so quickly from the lungs that enzymatic metabolism is less likely. This leaves as the most likely candidates for enzymatic metabolic reactions nonpolar lipophilic compounds , those that are relatively less soluble in aqueous biological fluids and more attracted to lipid species. Of these, the ones that are resistant to enzymatic attack (polychlorinated biphenyls (PCBs), for example) tend to bio-accumulate in lipid tissue. Xenobiotic species may be metabolized in a wide variety of body tissues and organs. As part of the body’s defense against the entry of xenobiotic species, the most prominent sites of xenobiotic metabolism are those associated with entry into the body. The skin is one such organ, as is the lung. The gut wall through which xenobiotic species enter the body from the gastrointestinal tract is also a site of significant xenobiotic compound metabolism. The liver is of particular significance because materials entering systemic circulation from the gastrointestinal tract must first traverse the liver.  III- METABOLISM Volatile toxic substances can enter the bloodstream through the lungs, a major pathway for environmental and occupational exposure to xenobiotic. Toxic substances can also be absorbed through the skin. Un-digested food residues and wastes excreted from the liver in bile leave the body through the intestinal tract as feces. The other major pathway for elimination of waste products from metabolic processes consists of the kidneys, which remove such materials from blood, and the bladder and urinary tract through which urine leaves the body. Waste carbon dioxide from the oxidation of food nutrients is eliminated through the lungs. Phase I and Phase II Reactions The processes that most xenobiotic undergo in the body can be divided into two categories: phase I reactions and phase II reactions. A phase I reaction: Introduces reactive, polar functional groups onto lipophilic (fat-seeking) toxicant molecules. In their unmodified forms, such toxicant molecules tend to pass through lipid-containing cell membranes and may be bound to lipoproteins, in which form they are transported through the body. -Because of the functional group attached, the product of a phase I reaction is usually more water soluble than the parent xenobiotic species, and more importantly, it possesses a “chemical handle” to which a substrate material in the body may become attached so that the toxicant can be eliminated from the body. The binding of such a substrate is a phase II reaction , and it produces a conjugation product that normally (but not always) is less toxic than the parent xenobiotic compound or its phase I metabolite and more readily excreted from the body. The following figure shows the overall processes involved in a phase I reaction. Normally a phase I reaction adds a functional group to a hydrocarbon chain or ring or modifies one that is already present. The product is a chemical species that readily undergoes conjugation with some other species naturally present in the body to form a substance that can be readily excreted. Phase I reactions are of several types, of which oxidation of C, N, S, and P is most important. Reduction may occur on reducible functionalities by addition of H or removal of O. Phase I reactions may also consist of hydrolysis processes, which require that the xenobiotic compound have a hydrolyzable group. III) EXCRETION : URINARY PH TRAPPING. Particularly at DCT, the non-ionized form is readily reabsorbed. Therefore, altering the pH of the urine can increase the toxicity of some medications. Moreover, modifying the pH of the urine chemically can either increase or decrease tubular drug reabsorption. Distal convoluted tubule (DCT). For example: Aspirin overdose can be treated by urine alkalinization with Na Bicarbonate (ion trapping) Ammonium chloride can be used as urine acidifier for basic drug (amphetamine) overdose treatment  III) EXCRETION:TUBULAR SECRETION In the proximal renal tubule: ▪ Organic anionic & cationic transporters (OAT & OCT) mediate active secretion of anionic & cationic drugs ▪ Penicillin is an example of actively secreted drugs ▪ Allopurinol competes with chlorpropamide secretion in renal tubes so increasing its half life & its hypoglycemic effect of  Thanks You