2. Toxicokinetics/dynamics Flashcards
Describe the development of toxicity after toxicant exposure.
- Person is exposed to toxicant
- Toxicokinetics: what happens from exposure to the point of action
- Toxicodynamics: Interaction with target molecules and how the toxicant exerts its effect on biological systsems
What is toxicokinetics?
The way the body handles toxicants. It is the modelling and mathematical description of the time course of disposition of toxicants. Disposition is also known as the “the movement and fate of a toxicant”. Therefore, Toxicokinetics is usually described with ADME except instead of a pharmaceutical compound its a toxicant so it is often referred to as ADMET.
What are the major routes of toxicant exposure? (absorption)
Major routes of toxicant exposure:
the skin, lungs and gastro-intestinal tract.
How are toxicants absorbed through the skin?
Toxicants cross the stratum corneum, in the epidermis (outer skin layer), by diffusion. The skin is not an impermeable membrane that prevents chemicals from coming through. The more lipophilic a substance is the more likely it will penetrate
Describe the absorption of toxicants via the lungs. What happens to gas molecules vs particles?
You inhale particles through your nose, which goes into the bronchioles, into the alveoli, and then into the blood and lymph.
- Gas molecules diffuse into the blood;
- Particles may be deposited in the tracheobranchial region; they may be swallowed, removed by phagocytosis, or by lymphatics.
A lot of conditions have been associated with particulate matter like cardiovascular system problems and cancers.
Describe particle absorption in the upper respiratory tract, the bronchioles, and the alveoli.
Upper (nasal, pharyngeal, laryngeal): Absorbs big and small particles
Tracheobronchial: mostly small particles absorbed
Alveolar: Still small particles but absorbed better than bronchial.
Describe the absorption of toxicants via the GI tract.
What does the rate of transport correlate with?
Most chemicals cross the GI epithelium by simple diffusion: Rate of transport correlates with lipid solubility.
It depends on the basicity and acidity (charge) of the GI tract, the more the toxicant is lipid soluble in that state, the more it is absorbed.
What is a specialized barrier and what is its effect on absorption?
A regular vessel will allow both lipid and water soluble molecule to cross.
A blood brain barrier has tight junctions so water soluble molecules won’t penetrate but lipid soluble molecules will.
Ex: blood brain barrier, eye barrier, blood testis barrier, oocyte barrier. But the last 3 have dynamics that change over time therefore some toxicants will be able to cross.
Is the placenta a barrier to toxicants?
The placenta is NOT a barrier. Just about anything the mother sees, the fetus will see.
How are toxicants distributed?
Once it comes into the body, it is taken around the body by the circulation.
How are toxicants metabolized?
Their major site of metabolism is in the liver and is done by enzymes through 4 types of reactions:
1) Hydrolysis
2) Reduction
3) Oxidation
4) Conjugation
Describe the 2 phases of the metabolism/biotransformation of toxicants.
Phase 1: Converts molecule so that it has a charge and can be more easily eliminated via oxidation, hydrolysis, and reduction.
Phase 2: Conjugation– adds things on via many enzymes to make it more polar and easily eliminated
ex: Sulfonation (sulfation), acetylation, and glucuronidation.
The major purpose of the 2 reactions is to transform a lipophilic molecule into a hydrophilic one so that it is more easily eliminated.
What is an example of a hydrolysis reaction?
Epoxide hydrolase is an enzyme that makes a really strained 3 membered ring called epoxide into a Diol which reacts with many cellular proteins and DNA. In this case the molecule made due to metabolism is more toxic than the starting molecule.
What’s an example of an oxidation reaction?
the metabolism of ethanol (alcohol) in the liver via:
- Alcohol dehydrogenase (ADH) which makes acetaldehyde (TOXIC) from ethanol.
- Aldehyde dehydrogenase (ALDH) which makes acetic acid from acetaldehyde.
ALDH is the rate limiting step. If it is blocked or saturated then acetaldehyde will accumulate which is toxic. This is another example of how a metabolite is more toxic than the initial compound.
Which enzymes perform the oxidation/reduction reactions? How can toxicants affect those enzymes?
Cytochrome P450s.
toxicants can affect p450s by turning them on, inhibiting them, and toxicants can also be converted by them.
What is significant about the metabolism of benzo[a]pyrene?
The metabolites that are made are really toxic, much more than the parent compound.
What are the types of conjugation reactions? which phase is it?
Phase 2: 1. Glucuronidation 2. Sulfonation (sulfation) 3. Acetylation 4. Methylation 5. Glutathione conjugation 6. Amino acid conjugation Many ways of modifying a molecule to make it less toxic and easily eliminated
Explain how glutathione conjugation works.
- Glutathione is a tripeptide with a free SH group which wants to bind electrophiles.
- Electrophile is rendered less toxic when it is bound bc it wont bind to other proteins or DNA and will be removed from the body (excreted).
What are the different ways toxicants can be eliminated? What is the major route?
- Fecal excretion
- Exhalation
- urinary excretion (major route)
Where and how does urinary excretion occur?
It occurs via the kidney. Different components in the renal tubule will allow for the concentration or removal of metabolites from the blood and into the urine.
The kidney also has several metabolizing enzymes but not as much as the liver.
