Mechanisms of toxicity V Flashcards
What are the three types of molecular repair
-Proteins
-Lipids
-DNA
Protein molecular repair
-oxidation of thiol (-SH) [Sulphur Hydro groups] groups is most common effect
-Repaired by thioredoxin and glutaredoxin, which donate electrons to reduce (repair) oxidized protein
What is another common effect of protein molecular repair
- denaturation (misfolding) of proteins due to chemical or physical insult
- repair is facilitated by “molecular chaperones” such as Heat shock proteins (HSPs)
What are molecular chaperones
they are sensors in cells that are induced response to stress, they are repairing damage in the protein by being the protein police. If the protein can’t be fixed then HSPs will ‘chaperone’ the protein to recycling type centre within the body
Molecular repair - 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 C are also involved
Recall: xenobiotics can be bioactivated to ______ that bind covalently to _____, forming “_____ _____” if DNA is not repaired this is a major mechanism of chemical _______
xenobiotics can be bioactivated to electrophiles that bind covalently to DNA, forming “DNA Adducts” if DNA is not repaired this is a major mechanism of chemical carcinogenesis
What is NER
Nucleotide excision repair
what is the most important process involved in such DNA repair
NER
What are the three enzymes involved in DNA molecular 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
Cellular Repair
-Cellular repair is not common; in most tissues the damaged cell dies (via apoptosis or necrosis) and a neighboring cell divides to replace it (mitosis)
- an exception is in peripheral neurons, where damaged axons can be repaired (does not occur in CNS)
-peripheral neuropathy ie. lead toxicity
Tissue Repair: Apoptosis
-“physiological cell death” or “programmed cell death”
What are the three highly evolutionarily conserved process involved in tissue repair
- tissue remodelling (ie your hands in utero look like mittens until there is tissue remodelling to create the fingers)
- Deletion of damaged cells
- Deletion of cells displaying errors during mitosis
Tissue repair apoptosis
what disease does decreased apop cause, what disease does increased apop cause
Important in many diseases; both decreased apoptosis e.g cancer, and increased apoptosis e.g. parkinson’s, alzheimer’s, HIV-AIDS, can play an important role
Tissue Repair - mitosis
-in most tissues, cells divide to replace cells deleted by apoptosis
- another example of a critical balance in toxicology: the apoptosis-mitosis balance
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Mitosis ^ Apoptosis (cancer) (neuro-
degeneration
diseases)
Apoptosis VS Necrosis:
Apoptosis
A: (Physiological)
“cell suicide”
Active, programmed
Single cells
Chromatin and cytoplasmic condensation, cell shrinkage
Hours
mRNA and protein synthesis
Normal ATP
No inflammation
specific endonuclease (DNase) activation
Internucleosomal DNA cleavage (“ladder”)
Lower doses
