Delivery. Delivery Processes. Delivery Processes: Distribution. Ultimate Toxicant

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1 Delivery Ultimate Toxicant The chemical species that reacts with the endogenous target. Toxicity depends on the concentration (dose) of the ultimate toxicant at the target site Delivery Processes Absorption vs. Presystemic Elimination Absorption: Epithelial barriers Rate of absorption Concentration, area, microcirculation, solubility Presystemic Elimination First Pass elimination Distribution Blood ECF Cells Target Delivery Processes: Distribution Facilitating Mechanisms Endothelium porosity Specialized transport Reversible intracellular binding Opposing Mechanisms Plasma Proteins Special barriers Storage sites Non-target binding Export

2 Delivery: Excretion vs Reabsorption Excretion Kidney & Liver Filtration Active transport Hydrophilicity vs. hydrophobicity Reabsorption Diffusion ph and weak acids and bases Delivery: Toxication vs. Detoxication Toxication Biotransformation to harmful products (bioactivation) Electrophiles Free radicals Nucleophiles Redox- active reactants Delivery: Toxication vs. Detoxication Detoxication Biotransformation to eliminate or prevent formation of ultimate toxicant. Toxicant without functional groups 2 phases that increase molecule polarity. Nucleophiles & electrophiles Free radicals SOD & Catalase Protein toxins proteases, antibodies

3 Reaction of Toxicant with Target: Attributes of targets Macromolecules vs small molecules Nucleic acids & Proteins Reactivity/stearic configuration highest conc. of toxicant or adjacent to site of formation. Critical Function Conclusion: to ID a target molecule as responsible for toxicity the ultimate toxicant must React and adversely affect function Reach an effective conc. at target. Altered target mechanistically related to toxicity Types of Reactions Non-covalent bonding H bonds, reversible Receptors, ion channels, enzyme reactive sites Covalent bonding irreversible, permanent alteration. Electrophilic toxicants to nucleophilic targets Neutral free radicals: OH, NO 2, Cl 3 C H-abstraction neutral free radicals RH + OH R H 2 O R-SH + OH R-S disulfides Electron transfer Oxidation Fe 2+ of hemoglobin Methemoglobin (Fe 3+ ) Enzymatic-like reactions: ricin fragmentation of ribosomes Effects On Targets Dysfunction of target molecules by mimicking ligands: Enzymes active site, conformational change Neurotransmitters Ion transporters DNA template interference for replication/transcription Destruction of target molecules by: cross linking - proteins Fragmentation proteins & nucleic acids Neoantigen formation

4 Cellular Dysfunction Definition: Interruption of cellular coordinated activity involving long term and short term cell programs. Regulatory networks Gene Expression Transcription Signal transduction Signal production Dysregulation Ongoing cell activity of specialized cells Interference with second messangers; Ca, camp Electrically Excitable Cells- neurons, muscle Neurotransmitter level alterations Neurotransmitter receptor interaction Signal transducer interactions Signal terminator interactions Dysregulation Alteration of cellular maintenance Internal cellular maintenance ATP synthesis Class I H delivery to e - transport chain Class II e - transfer to O 2 Class II - O 2 delivery to terminal e - transporter Class IV ATP synthase Control of intracellular Ca + levels Mitochondrial interference Ca + transport mechanisms

5 Dysregulation Extracellular maintenance Interference with cells/tissues that support other cells/tissues Hepatocyte toxicity blood proteins & nutrients Molecular Repair Proteins reversing oxidative damage to thiols. Thioredoxin, Glutaredoxin, Methemoglobin reductase Lipids repair of peroxides DNA Direct repair Photolyase Excision repair base excision & nucleotide excision Recombinational (postreplicational) repair Cellular Repair Not a widely applied repair strategy Highly differentiated cells, i.e. neurons Nervous system repair Peripheral Nervous system cellular cooperation involving macrophages & Schwann cells CNS irreversible damage inhibitory glycoproteins, chondroitin sulfate proteoglycans, astrocytes.

6 Tissue Repair Deletion & proliferation Apoptosis vs. necrosis Proliferation: regeneration of tissue, a complex process Replacement of ECM Side Reactions to Tissue Injury Inflammation Alteration of circulation Accumulation of inflammatory cells Enhanced release of cytokines TNF, Il1 Respiratory burst ROS, RNS, hydrolytic enzymes Altered Protein synthesis acute phase proteins Il6, Il1, & TNF stimulate +/- proteins via TFs Failure of Repair Lack of fidelity Damage overwhelms repair & repair processes are exhausted Inhibition of potentially proliferating cells Un-repairable damage covalent binding of toxicants Repair processes compromise oxidative phosphorylation - NAD or NAD(P)H

7 Toxicity Resulting form Dysrepair Tissue necrosis Caused by inefficient repair and/or irreversible damage Counteracted by: Apoptosis & cell proliferation Fibrosis excessive deposition of ECM/scar tissue Compression of tissue cells and blood vessels Diffusion barrier Elasticity & flexibility Cell functional properties polarity, motility, gene expression Toxicity Resulting form Dysrepair Carcinogenesis Failure of DNA repair/misrepair Mutation of protooncogenes Mutation of tumor suppressor genes Failure of apoptosis Failure to terminate proliferation