2 mechanisms of toxivity IV Flashcards
what is the outline of this lecture?
impaired cellular maintenance
a) mechanisms of toxic cell death
b) impaired external cellular maintenance
what are the mechanisms of toxic cell death?
i. impaired ATP synthesis
ii. sustained rise of intracellular Ca2+
iii. other mechanisms of cell death
what are the ways of impaired ATP synthesis?
review: oxidative phosphorylation (ATP synthesis)
A. delivery of hydrogen to electron transport chain (ETC) in the form of NADH
B. impaired function of ETC
C. impaired delivery of O2 as terminal electron acceptor
D. inhibition of ADP phosphorylation
what is the A inhibitor?
delivery of hydrogen to electron transport chain (ETC) in the form of NADH
-ex: arsenite inhibits pyruvate dehydrogenase (PDH complex) converting pyruvate to acetyl-CoA
-ex: fluoroacetate (rodenticide) inhibits enzymes aconitase in the citric acid cycle
what is the B inhibitor?
impaired function of ETC
-ex: rotenone (pesticide) inhibits NADH-coenzyme Q reductase (Complex I)
what is the C inhibitor?
impaired delivery of O2 as terminal electron acceptor
-ex: carbon monoxide (CO) displaces O2 on hemoglobin
what is the D inhibitor?
inhibition of ADP phosphorylation
-ex: chlordecone (pesticide) inhibits ATP synthase
ex: xenobiotics that “uncouple” (disrupt) the electrochemical (proton) gradient across inner mitochondrial membrane, which is the “driving force” for ATP synthase
-pentachlorophenol (fungicide) is an ionophore that causes protons to “leak” back into inner mitochondrial matrix
-dinitrophenol (herbicides) donate protons to inner mitochondrial matrix
what is the sustained rise of intracellular Ca2+?
-calcium ion is maintained at a 10,000x greater concentration extracellularly than intracellularly; disruption of Ca homeostasis is a major mechanism of toxic cell death
-Ca homeostasis is maintained by active transport from the cytoplasm to extracellular space by sequestration from cytoplasm into mitochondria and endoplasmic reticulum (ER)
what do xenobiotics act to do in the sustained rise of intracellular calcium?
-promote influx or inhibit efflux from cytoplasm
-cause “leakage” from mitochondria and ER into cytoplasm
what are the other mechanisms of cell death?
disrupt protein synthesis
-ex: ethanol
destroy cytoskeleton, specifically microtubules involved in mitosis and other cellular functions
-ex: colchicine (chemotherapy drug)
direct damage to plasma membrane
-ex: nonpolar solvents, detergents, and reactive oxygen species (ROS)
what is impaired external maintenance?
“Impaired function of integrated systems”
-inhibition of hepatic synthesis of coagulation factors
-ex: warfarin (rodenticide and blood thinner drug) inhibits activation of vitamin K needed for production of clotting factors
