2 mechanisms of toxicity V Flashcards
what is the fourth step?
IMPAIRED REPAIR PROCESSES (dose defines the poison)
1. molecular repair
2. cellular repair
3. tissue repair
what is molecular repair?
proteins
lipids
DNA
what is the molecular repair of proteins?
-oxidation of thiol (-SH) groups is most common effect (how alot of heavy metals cause toxicity by binding to thiol groups)
-repaired by thioredoxin and glutaredoxin, which donate electrons to reduce (repair) oxidized proteins (want out cells to remain in a reduced state, balance between oxidized and reduction), electrons come from NADPH
-another common effects is denaturation (misfolding) of proteins due to chemical (like electrophiles) or physical insult (like radiation)
-repair is facilitated by “molecular chaperones” such as heat shock proteins (HSPs) (chaperone to recycling bin to get reused)
what is molecular repair in lipids?
-oxidation of membrane lipids causes lipid peroxidation, which damages membranes and results in altered cellular homeostasis
-complex repair process facilitated by enzymes glutathione peroxidase and glutathione reductase; vitamin E and vitamin C are also involved (key reasons why want to eat veggies and fruits)
what is molecules repair of DNA?
-recall: xenos can be bioactivated to electrophiles that bind covalently to DNA, forming “DNA adducts (covalently bond)”; if DNA is not repaired this is a major mechanism of chemical carcinogenesis
-nucleotides excision repair (NER) is most important process involved
what are the three enzymes involved in molecular repair of DNA?
three enzymes involved in NER (nucleotide excision repair):
-endonuclease: “snips” out sequence of damaged DNA (including xenobiotic)
-DNA polymerase: synthesizes replacement strand of DNA
-DNA ligase: “glues” the new strand into DNA
what is cellular repair?
-is not common; in most tissues, the damaged cell dies (via apoptosis or necrosis) and a neighboring cell divides to replace it (liver cells will mitos to replace missing liver)
-an exception is in peripheral neurons, where damaged axons can be repaired (does not occur in the CNS) (many toxic metals cause neuropathy in peripheral nerves, like lead)
what is tissue repair?
-apoptosis
-mitosis
-necrosis
what is apoptosis (tissue repair)?
-also known as “physiological cell death” or “programmed cell death”
-highly evolutionarily conserved process involved in (1) tissue remodeling (fingers in thalidomide), (2) depletion of damaged cells, and (3) deletion of cells displaying errors during mitosis (phases have ways to stop mitosis)
-important in many disease; both decreased apoptosis (ex: cancer) and increased apoptosis (ex: Parkinson’s, Alzheimer’s, HIV, AIDS) can play an important role
-in normal body, 2 billion cells undergo apoptosis
what are the differences of apoptosis and necrosis?
necrosis: cell loses ability to maintain ion gradient so keeps swelling and ruptures
-when ATP decreases alot (dose), more cells die
what is mitosis?
-in most tissues, cells divide to replace cells deleted by apoptosis
-another example of a critical balance in toxicology; the apoptosis-mitosis balance
what does stimulation of cell death involve?
involves the complex relationships among cellular signals
-mitochondria act as cellular “sensors” and release signals to initiate cell death
mechanisms of _______________ are evolutionarily conserved from worms to humans?
apoptotic cell death
what is toxicity resulting from repair failure?
toxicity usually occurs when damage overwhelms repair mechanisms, although repair mechanisms are not perfect
-necrosis
-fibrosis
-carcinogenesis
what is necrosis?
-occurs when xeno exposure overwhelms (1) the repair of damaged proteins, DNA and/or lipids, (2) the elimination of damaged cells by apoptosis, and/or (3) the replacement of lost cells by mitosis
-higher dose effect
what is the summary graph of this lecture?
what is the review graph of the toxicology paradigm?
