toxicology lecture 4

• Xenobiotics


  Any foreign chemical to the human body - mainly anthropogenic, can be drugs, chemicals, pesticides, waste, food byproducts, etc.
• Bioavailability


  Fraction of an administered dose of unchanged drug that reaches systemic circulation → how much of the drug gets into the body completely unchanged and has some sort of effect or may metabolize into something else
• Toxicokinetics


  What the body is doing to the chemical (ADME)
• Toxicodynamics


  What the chemical is doing to the body
• Bioaccumulation


  Can occur when a xenobiotic is lipophilic and chemically stable - can easily store in fats and tissues, and persist for a long time

  
  

  when a substance builds up(accumulates) in a living organism. This happens when xenobiotics (substances) is both oily and stable, so it can stick around in fats and tissues. If an organism keeps getting exposed to the substances (xenobiotics), it will keep going up.
• Bioaccumulation


  1. Organism continuously exposed to an organic xenobiotic, its concentration in the whole organism will increase over a period of time

  2. Rate of increase in the tissue concentration of the xenobiotic will be rapid, but will then decline → will stay in system and potentially do damage

  
• Biomagnification


  Uptake of chemical residues through one successive level in the food chain, starting from the smallest trophic level

  
  

  is when chemicals like mercury become more concentrated as they move up from the food chain. This happens with chemicals that stick around the body for a long time, like ones with a long-half life or ones that dont break down easily.

  
• Biomagnification


  • Mercury is methylated, which makes it toxic, and it makes its way up through the food chain; it can persist in the body because the methyl group drops off and the mercury is stuck in tissue
• Biotransformation


  Refers to the enzymatic modification of chemicals within an organism, primarily in the liver
• Biotransformation


  • Plays a crucial role in maintaining homeostasis
  • It is essential in the fields of toxicology and pharmacology
• Biotransformation


  1. Involves a series of enzymatic reactions that transform xenobiotics into metabolites (typically occur in the liver)

  2. Enzymes convert chemicals → polar, water soluble compounds

  3. Highly water soluble chemicals → do not require biotransformation

  
• Objective of biotransformation


  One of the primary objectives is to facilitate the excretion of toxic substances from the body
• Objective of biotransformation

  1. Urine and feces go out of the body, bile recirculates and is excreted

  2. Bile has different pathways in the body
• Toxicology

  • Convert toxic compounds into less harmful forms, thus reducing their toxicity
  • Can also have the opposite effect (less harmful turned toxic) → related to the concept of bioactivation in pharmacology
• Pharmacology

  • Biotransformation can activate prodrugs → converting the drugs into an active, therapeutic form
  • It influences the pharmacokinetics of drugs, affecting efficacy and duration of actions
• Detoxification


  • Aims to convert harmful substances into less toxic forms
  • Preventing the accumulation of dangerous compounds in the body
• Detoxification


  • The detoxification of environmental toxins and drugs
  • The body detoxifies us everyday; cannot force yourself to "detox"
  • Detoxification centres are not about forcing things out of the body, it is rather complementary therapy for hydration, electrolytes, etc. in order for the body to carry out its processes, but it is not forcing the body to do anything faster → just medically monitoring
• Bioactivation


  • Involves the conversion of prodrugs into their active forms
  • Enhances therapeutic effects of medication
• Bioactivation

  • Prodrug activation in the treatment of cancer or hypertension
  • A lot of chemotherapeutic agents on their own are toxic but when out into the body at a slow rate of particular doses, they will bioactivate
  • The compound that fights the cancer directly will then do its job
• ADME process


  ADBE process (M is Biotransformation)
• Phase I reactions


  Increase the polarity of substrates
• Phase II reactions


  • Polar groups are added to the products of phase I reactions
  • Make compounds more polar; add polar groups to the products/metabolites of the phase I reaction
• Enzyme Commission Numbering System

  • Taking something lipophilic and making is hydrophilic
  • Hydrophilic compounds are water soluble
• Toxicant types


  • Highly lipophilic, metabolically stable → pose the most risk for the most part
  • Lipophilic → aren't necessarily metabolically stable (can't persist in the body for as long)
  • Polar → more water-like but may require some phase reaction in order to be excreted from the body
  • Hydrophilic → are eliminated as quick as possible (elimination is assuming whatever you've been exposed to hasn't killed you)

  
• Biotransformation process


  1. Exposed to a xenobiotic → goes to phase I and/or II in no particular order

  2. Very dependent on the xenobiotic

  3. Upon exposure, the xenobiotic goes through the first pass effect in the liver

  4. The potential of oxidizing, reducing, or hydrolyzing the xenobiotic itself

  5. If the metabolite has high polarity and is soluble in water, it is hydrophilic and can be excreted through bile and through urine in the kidneys

  6. If the metabolite isn't polar or highly soluble in water, it goes through a phase II reaction

  7. Conjugated metabolite → adding another group

  8. If it can't reach this point, it will persist in the body and can cause problems

  9. Lipophilicity eases the introduction of a xenobiotic into the body → easier absorption overall (GI tract, skin, lungs, etc.)

  10. This is an obstacle to elimination
• Cytochrome P450


  Major metabolic route for phase I reactions

  
• Liver


  Main site of biotransformation and the first pass effect
• Other sites of biotransformation

  • Proximal tubule of the kidneys
  • Type 2 cells of the lungs
  • Gut flora of the intestine
  • Testes; sertoli cells
  • Skin; epithelial cells
  • Breasts; breast milk → pathway of exposure to toxicants and biotransformation for infants being breastfed
• Phase I metabolism


  • Involves functionalization reactions
  • Making something that is modified; modifying a chemical to make it more polar and water soluble

  
• Phase I reactions


  • Hydrolysis: adding a hydroxyl (-OH) group to a molecule
  • Oxidation: the loss of electrons from a molecule; adding an oxygen, removing a hydrogen to increase the electric charge of the compound
  • Reduction: the gain of electrons by a molecule; removing an oxygen and adding a hydrogen to decrease the electric charge
• Cytochrome P450 (CYP) enzymes

  • Cyto = of a cell; chrome = colour, that is P450 and refers to maximum absorbance of light that occurs at 450 nanometers
  • A superfamily of heme-containing proteins found in various organisms
  • Involved in metabolism of a wide range of compounds, including drugs, toxins, environmental pollutants, etc.
  • Catalyze diverse reactions, such as hydroxylation, oxidation, and reduction, thereby facilitating the transformation of lipophilic substances into more water-soluble metabolites
  • Enzymes are crucial in the metabolism of toxins and also pharmacological drugs
  • Over 1000 different genes and enzymes identified in the family
  • Found in most tissues, with the highest concentration in liver cells, hepatocytes
  • Membrane-bound proteins primarily located in the endoplasmic reticulum (ER)

  
• CYP: Structure and Function

  • Enzymes are characterized by heme-binding domain, which is why there is iron seen in these reactions
  • Active site of CYP450 (middle) accommodates various substrates, allowing them to metabolize a diverse array of compounds
  • Activity of enzymes can be influenced by genetic polymorphisms, changes in genes, environmental factors, drug interactions, lifestyle, etc. which can all lead to inter-individual variability in response to toxins
  • Not born with CYP3A4; it generates as you grow; there are very specific ways of administering medications among neonates because of the different metabolic pathways that don't exist

  
• Enzymes


  Found in most tissues, with the highest concentration in liver cells, hepatocytes
• Enzymes


  • Membrane-bound proteins primarily located in the endoplasmic reticulum (ER)
• CYP


  Enzymes characterized by heme-binding domain, which is why there is iron seen in these reactions (heme is part of hemoglobin)
• Heme binding to oxygen


  Creates a form of hemoglobin to transfer oxygen to other parts of the body
• Active site of CYP450

  Accommodates various substrates, allowing them to metabolize a diverse array of compounds
• Activity of enzymes can be influenced by genetic polymorphisms, changes in genes, environmental factors, drug interactions, lifestyle, etc. which can all lead to inter-individual variability in response to toxins
• CYP3A4 is not present at birth; it generates as you grow; there are very specific ways of administering medications among neonates because of the different metabolic pathways that don't exist

  
• Genetic Variation


  • Polymorphisms in Phase I enzyme genes → inter-individual differences in enzyme activity
  • Can affect drug response and metabolism