Cytotoxicity, Tissue Injury, and Target Organs

• Cytotoxicity


  The quality of being toxic to cells
• Cytotoxicity

  • Involves mechanisms
  • Critical for evaluating the safety and therapeutic efficacy of pharmaceuticals
• Cell injury

  Cells control their environment and intracellular milieu within physiological parameters for homeostasis
• Agents of cell injury


  • Oxygen
  • Physical agents
  • Chemical agents
  • Infectious agents
  • Immunologic reactions
  • Genetic defects
  • Dietary factors
• Mechanisms of cellular injury


  1. Disruption of cellular membranes

  2. Inhibition of protein synthesis

  3. Indirect cellular damage
• Reactive oxygen species (ROS)


  Superoxide, hydrogen peroxide, hydroxyl radical

  
• Free radicals

  • Chemical characteristics
  • Mechanisms of formation: endogenous and exogenous sources
  • Roles in normal cellular functions and pathological conditions

  
• Intracellular sources of free radicals

  • Enzymes
  • Normal redox reactions
  • Nitric oxide
  • Ionizing radiation
  • Metabolism of CCl4

  
• Oxidative stress and ROS


  • Life developed in the presence of approximately 20% oxygen
  • Oxygen forms free radicals

  
• Cellular responses to ROS damage

  1. Antioxidant defense mechanisms

  2. Signal transduction pathways

  3. Cell death pathways: apoptosis, necrosis, autophagy

  
• Role of ROS in disease


  • Contribution to cancer, cardiovascular diseases, and neurodegeneration
  • Dual role in cell signaling and disease progression
• Antioxidant defense mechanisms


  • Glutathione
  • Superoxide dismutase
  • Catalase
• Reducing oxidative stress


  • Lifestyle and dietary modifications
  • Pharmacological interventions: antioxidants and free radical scavengers
  • Advances in targeted therapies
• Necrosis

  ROS impact varies by dose: low dose - growth arrest, senescence; intermediate - mitogenic, proliferative, regulation of gene expression; high dose - cell death

  
• Etiology of tissue necrosis


  • Hypoxia
  • Physical injury
  • Chemicals
  • Biological toxins
  • Immunological reactions
  • Genetic disorders
  • Nutritional factors

  
• Mechanisms of necrosis


  • Signs of necrosis
  • Types of necrosis
• Autophagy


  A cellular process for degrading and recycling cellular components
• Acute injury

  Rapid onset, severe but short-lived symptoms
• Chronic injury


  Results from prolonged exposure, gradual development and persistent symptoms
• Tissue repair (healing)


  1. Regeneration of injured tissue

  2. Replacement by fibrous tissue (fibrosis, scarring)
• Regeneration


  The ability of a tissue to replace damaged cells with new cells of the same type, key to restoring original structure and function
• Fibrosis


  The replacement of damaged tissue with scar tissue, composed mainly of collagen
• Type of toxicant and exposure

  • The chemical nature of the toxicant can determine the type and severity of tissue injury
  • Both the dose and duration of exposure are critical
• Susceptibility and genetic factors


  • Genetic makeup can influence an individual's ability to metabolize or detoxify harmful substances
• Target organs


  Specific organs or tissues most affected by exposure to a particular toxicant
• Toxicant distribution to target organs

  1. Toxicant enters the blood

  2. Circulates in the body

  3. Enters cells

  4. Distribution to the targets may be enhanced by porosity, transport, receptors, binding
• Opposing distribution to a target organ

  1. Binding to plasma proteins

  2. Specialized barriers

  3. Distribution to storage site

  4. Association to intracellular binding proteins

  5. Export from cells
• Metabolic activation - liver injury

  • Liver metabolizes toxic substances; lipophilic compounds to hydrophilic
  • Examples include the metabolism of acetaminophen into NAPQI
• Oxidative stress in hepatotoxicity


  • Reactive oxygen species (ROS) produced during metabolism
  • Excessive ROS → oxidative stress, damaging lipids, proteins, DNA
  • Overwhelmed antioxidant defense → cell injury, death

  
• Immune-mediated liver damage


  • Liver: immune surveillance, site of immune-mediated damage
  • Hepatotoxicants alter liver cell antigens, induce neoantigens
  • Immune attack → inflammation, hepatocyte destruction (e.g., DILI)
• Direct toxin effects on renal cells

  • Kidneys highly vascularized, exposed to circulating toxicants
  • Direct toxicity → acute tubular necrosis, AKI
  • Common causes: antibiotics (aminoglycosides), heavy metals (mercury)

  
• Nephrotoxicity

  • Glomeruli filter blood, damage impairs kidney function
  • Toxicants cause glomerulonephritis, proteinuria, reduced filtration
  • Immune responses to infections, diseases can also damage glomeruli

  
• Obstruction of urinary pathways

  • Drugs, toxins precipitate in kidneys, form crystals

  
• Reactive oxygen species (ROS)


  • Excessive ROS → oxidative stress, damaging lipids, proteins, DNA
  • Overwhelmed antioxidant defense → cell injury, death

  
• Immune-mediated Liver Damage


  • Liver: immune surveillance, site of immune-mediated damage
  • Hepatotoxicants alter liver cell antigens, induce neoantigens
  • Immune attack → inflammation, hepatocyte destruction (e.g., DILI)
• Direct Toxin Effects on Renal Cells


  • Kidneys highly vascularized, exposed to circulating toxicants
  • Direct toxicity → acute tubular necrosis, AKI
  • Common causes: antibiotics (aminoglycosides), heavy metals (mercury)

  
• Nephrotoxicity


  • Glomeruli filter blood, damage impairs kidney function
  • Toxicants cause glomerulonephritis, proteinuria, reduced filtration
  • Immune responses to infections, diseases can also damage glomeruli

  
• Obstruction of Urinary Pathways

  • Drugs, toxins precipitate in kidneys, form crystals
  • Obstruction leads to hydronephrosis, renal failure
  • Examples: uric acid crystals in malignancy treatment, sulfonamides

  
• Inhalation of Toxins and Particles

  • Lung's direct interface with environment → susceptible to inhaled toxicants
  • Acute exposure to irritant gases (e.g., chlorine, ammonia) → pulmonary edema, ARDS
  • Chronic exposure to particulate matter (e.g., silica, asbestos) → COPD, fibrosis
• Respiratory Toxicity


  • Inhalation of toxicants → inflammatory response, chronic inflammation, tissue damage
  • Persistent inflammation → exacerbate pre-existing conditions (e.g., asthma), bronchitis, pulmonary fibrosis
  • Long-term exposure to air pollutants (e.g., fine particulate matter, ozone) → significant risk factor