Complete presentation MES106 Unit 1 part b.pptx

Complete toxicity note

1. Mechanism of Toxicity

2. Importance of understanding Mechanisms of toxicity 1) Estimation of the possible harmful effects by chemicals 2) Establishment of procedures that prevent or antagonize the toxic effects 3) Designing drugs and industrial chemicals those are less hazardous 4) Mechanistic understanding helps the governmental regulator to establish legally binding safe limits for human exposure.  5) Mechanistic knowledge is also useful in forming the basis for therapy and the design of new drugs for treatment of human disease.

3. Mechanisms of Toxicity Step1- Delivery from the site of exposure to the target Step2- Reaction of the ultimate toxicant with the target molecule Step3- Cellular dysfunction and resultant toxicities Step 4- Repair or Disrepair

4. Step1- Delivery from the site of exposure to the target Delivery is the movement of the toxicant from the site of exposure to the site of its action Intensity of a toxic effect depends on the concentration & persistence of the ultimate toxicant at its site of action. Ultimate toxicant is the chemical that reacts with the endogenous target molecule (e.g. receptor, enzyme, DNA, protein, lipid) or critically alters the biological environment, initiating structural and/or functional alterations that result in toxicity.

5. Factors affecting Delivery Absorption Distribution toward the target Reabsorption Toxication Presystemic elimination Distribution away from the target Excretion Detoxication

6. EXPOSURE SITE Skin, Inhalation, Injection TOXICANT     D E L I V E R Y ULTIMATE TOXICANT TARGET MOLECULE Protein, Lipid, Microfilament, DNA, Receptor Absorption Distribution toward the target Reabsorption Toxication Presystemic elimination Distribution away from the target Excretion Detoxication

7. Absorption versus Presystemic Elimination Absorption is the transfer of a chemical from the site of exposure into the systemic circulation. The rate of absorption is related to: The concentration of the chemical at the absorbing surface, which depends on the rate of exposure and the dissolution of the chemical. The area of the exposed site The characteristics of the epithelial layer through which absorption takes place (e.g., the thickness of the stratum corneum in the skin) The intensity of the subepithelial microcirculation The physicochemical properties of the toxicant: lipid solubility is usually the most important property influencing absorption. In general, lipid-soluble chemicals are absorbed more readily than are water-soluble substances.

8. Presystemic Elimination means removal of the toxicant during its transfer from the site of exposure to the systemic circulation. Such processes may prevent a considerable quantity of chemicals from reaching the systemic blood.

9. Distribution to and Away from the Target During the distribution phase toxicants enter the extracellular space and may penetrate into cells. Lipid-soluble compounds move readily into cells by diffusion. Highly ionized and hydrophilic xenobiotics (e.g. aminoglycosides) are largely restricted to the extracellular space unless specialized membrane carrier systems are available to transport them .

10. Distribution to and Away from the Target During distribution, toxicants reach their site or sites of action, usually a macromolecule on either the surface or the interior of a particular type of cell. Chemicals also may be distributed to the site or sites of toxication , usually an intracellular enzyme, where the ultimate toxicant is formed.

11. Mechanisms Opposing Distribution to a Target Binding to plasma proteins : xenobiotics such as DDT cannot leave capillaries by diffusion because they are bound to plasma lipoproteins. Specialized barriers : brain capillaries lack fenestrae and are joined by extremely tight junctions. They prevent the access of hydrophilic chemicals to the brain except for those that can be actively transported. Accumulation in storage (as adipose tissue) : some chemicals accumulate in tissues (i.e., storage sites) where they do not exert significant effects. Highly lipophilic substances as chlorinated hydrocarbon insecticides concentrate in adipocytes lead is deposited in bone by substituting for Ca 2+ in hydroxyapatite.

12. Excretion versus Reabsorption Excretion is the removal of xenobiotics from the blood and their return to the external environment. Excretion is a physical mechanism whereas biotransformation is a chemical mechanism for eliminating the toxicant. The route and speed of excretion depend on the physicochemical properties of the toxicant.

13. Excretion versus Reabsorption (cont.) The major excretory organs—the kidney and the liver—can efficiently remove only highly hydrophilic, usually ionized chemicals such as organic acids and bases. Nonvolatile chemicals are excreted by kidneys Volatile toxicants such as gases are exhaled through alveoli

14. Excretion versus Reabsorption (cont.) Reabsorption is the reuptake of filtrated toxicants by renal tubules across their tubular cells into the peritubular capillaries. Reabsorption by diffusion is dependent on the lipid solubility of the chemical. For organic acids and bases, diffusion is inversely related to the extent of ionization, because the non ionized molecule is more lipid-soluble.

15. Toxication versus Detoxication Toxication ( metabolic activation): biotransformation to harmful products. Most often, T oxication makes xenobiotics reactive toward endogenous molecules with susceptible functional groups. Sometimes , Toxication may have physicochemical properties to alter micro environment of biological processes or structures. e.g , oxalic acid formed from E. glycol may cause acidosis. Occasionally , chemicals acquire structural features and reactivity by biotransformation that allows for a more efficient interaction with specific receptors or enzymes.

16. Toxication (cont.) Increased reactivity may be due to conversion into Free radicals Formation of Nucleophiles Redox-active reactants

17. Detoxication Biotransformations that eliminate the ultimate toxicant or prevent its formation Detoxication of Toxicants with No Functional Groups : chemicals without functional groups, such as benzene and toluene, are detoxicated in two phases.

18. Step2- Reaction of the ultimate toxicant with the target molecule This reaction leads to the injury to the target molecule itself, cell organelles, cells, tissues and organs, and even the whole organism. The reaction of the ultimate toxicant with the target molecule is affected by: Characters of target molecules : the most common targets are macromolecules such as nucleic acids and proteins. Among small molecules, membrane lipids are frequently involved. Types of reactions between ultimate toxicants and target molecules : Bind to the target molecules Alter it by hydrogen removal, electron transfer, or enzymatically. Effects of toxicants on the target molecules : reaction of the ultimate toxicant with endogenous molecules may cause dysfunction or destruction; in the case of proteins, it may render them foreign (i.e., an antigen) to the immune system.

19. Step3- Cellular dysfunction and resultant toxicities The reaction of toxicants with a target molecule may result in impaired cellular function. Normally, each cell has defined programs: Programs determine the destiny of cells —that is, whether they undergo division, differentiation (i.e., produce proteins for specialized functions) or apoptosis Programs control the activity of differentiated cells , determining whether they secrete more or less of a substance, whether they contract or relax, and whether they transport and metabolize nutrients at higher or lower rates.

20. Step 4- Repair or Dysrepair Many toxicants alter macromolecules, which, if not repaired, cause damage at higher levels in the organism. The organism trials to repair the damaging effects from toxicants on molecular, cellular, and tissue levels

21. Molecular Repair damaged molecules may be repaired in different ways: Chemical alterations, such as oxidation of protein thiols , are simply reversed. Hydrolytic removal of the molecule's damaged unit and insertion of a newly synthesized unit often occur with chemically altered DNA Re synthesis of the damaged molecule

22. Cellular Repair Repair of damaged cells is not a widely applied strategy in overcoming cellular injuries. In most tissues, injured cells die. An exception is nerve tissue, because mature neurons have lost their ability to multiply. In peripheral neurons with axonal damage, repair may occur.

23. Tissue Repair Occurs in tissues with cells capable of multiplying Damage is reversed through regeneration of the tissue by proliferation. The damaged cells are eliminated by apoptosis or necrosis.

24. Dysrepair (failure of repair) may occur due to various reasons: Rate of damage is more than repair Exhaustion of repair mechanisms due to consumption of necessary enzymes or cofactors by the damaging process. Injury of the repair process itself such as blockage of mitosis of surviving cells will prevent tissue restoration.