Mechanisms of Toxicity

1. Mechanisms of Toxicity

2. Stages in Development of Toxicity Delivery of toxicant from the site of exposure to the target tissue/site Reaction of the toxicant with the target molecule Cellular dysfunction and resulting toxicity Repair or dysrepair

4. Delivery of Toxicant to Target Site Four primary factors affecting delivery: Absorption Distribution Excretion Biotransformation

6. Absorption Transfer of the toxicant/chemical from the site of exposure into the systemic circulation Lipid solubility First pass elimination

7. Distribution Movement of toxicants from the bloodstream into the ECF and/or tissues Facilitation Porosity of capillary endothelium Transport across membranes Inhibition Binding to plasma proteins Tight junctions Storage/intracellular binding proteins

8. Excretion Removal of xenobiotics from blood to the external environment Major organs Kidney and liver Highly hydrophilic chemicals removed efficiently Reabsorption Lipophilic

9. Biotransformation Metabolism or detoxication of chemicals into forms that are easily excreted Hydrophilic Toxication or Metabolic activation Metabolism results in a harmful product Common reactive metabolites Electrophiles Free radicals Nucleophiles Redox-active reactants

10. Reaction of Toxicant with Target Toxicant reacts with endogenous compounds Nucleic acids Proteins Membranes Types of Reactions Noncovalent binding Covalent binding Hydrogen abstraction Electron transfer

11. Effects on Target Molecules Dysfunction of target molecules Activate or inhibit target molecules Mimic endogenous ligands Block receptors, ion channels or enzymes Alter structure of proteins Interfere with transcription/translation of DNA Destruction of target molecules Adduct formation Cross-linking and fragmentation Alteration of the microenvironment

13. Cellular Dysfunction Gene expression Transcription Interaction with promotor gene, transcription factors (TFs) Signal transduction Activation of TFs via intracellular signaling networks Promote mitosis and tumor formation

14. Cellular Dysfunction Ongoing cellular activity Electrically excitable cells Alteration of neurotransmitter levels Alteration of receptor-ligand interactions Alter signal transduction Voltage gated Na+ channels Inhibition of transporter molecules

15. Cell Death Necrosis Degenerative process leading to cell death Usually localized to specific tissue or organ Cellular changes Karyolysis Nuclear disintegration Mitochondria swell More granules Cytoplasmic changes

16. Cell Death Apoptosis Programmed” cell death Cell shrinkage Nuclear fragmentation Not associated with inflammation

17. Mechanisms of Cell Death Depletion of ATP Interference with the delivery of H+ to ETC Inhibition of electron transfer along ETC Interference with oxygen delivery Inhibition of ATP synthase Sustained rise in intracellular Ca++ Influx into cytoplasm Inhibition of Ca++ export

19. Mechanisms of Cell Death Excess intracellular calcium Inhibits ATPase in oxidative phosphorylation Dysfunction of microfilaments Generation of reactive oxygen and nitrogen species (ROS, RNS) Mitochondrial permeability transition ? mitochondrial inner-membrane permeability Stops ATP synthesis

21. Cell Repair Repair of proteins and lipids DNA repair Excision repair Apoptosis Proliferation ONLY cells capable of dividing!

22. Dysrepair Rate of injury exceeds rate of repair! Necrosis Fibrosis Carcinogenesis Failure of DNA repair Failure of apoptosis