7. Kane lecture 11/10 – Flashcards

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3 targets of oxidant attack
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proteins, lipids, DNA
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what happens when oxidants attack lipids? (2)
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1. peroxidation of plasma and intracellular membranes (phospholipids, mitochondrial membrane etc.), 2. free radicals attack double bonds of unsaturated fatty acids
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what makes oxidant attack on lipids so dangerous?
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it's a chain reaction that keeps propagating
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final blow resulting in irreversible injury to a cell
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peroxidative damage to the plasma membrane permeability barrier
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what happens when oxidants attack DNA? (3)
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1. oxidation of bases, 2. DNA crosslinks, 3. DNA breaks
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what type of cell damage causes cancer? in absence of what?
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oxidative damage to DNA, in absence of adequate cell repair mechanisms
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p53 basics, not actions (3)
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1. protein that is a major regulatory switch in the cellular response to oxidant-induced DNA damage. 2. a nuclear phosphoprotein. 3. a sensor of DNA damage
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mutation in p53 gene
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leads to cancer (no DNA repair)
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when p53 is activated, what does it do?
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1. binds to DNA, 2. transcriptionally up-regulates genes for p21, GADD45 and BAX
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what activates p53? (2)
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DNA damage and hypoxia
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what regulates which gene (that is activated by p53) wins?
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the extent of the DNA damage
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p21
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CDK inhibitor that promotes cell cycle stage G1 arrest, leading to successful repair (along with GADD45)
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where is p53 located?
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in the cytoplasm. in response to DNA damage, it stabilizes and translocates to the nucleus.
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risk=
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hazard x exposure! Paracelsus: 15th century, "the dose makes the poison"
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carbon tetrachloride (2) / site of attack (4)
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1. like ethanol, becomes toxic when metabolized. 2. halogenated hydrocarbon. / the organ where metabolism occurs - usually the liver - or site of excretion of the reactive metabolites - kidney or bladder.
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cytochrome P450 mixed function oxidase system
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= a major site of drug and chemical metabolism
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hydrocarbons
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CCl4 is one. they are abundant as fuels, paints, cleaners, lubricants, rubber cement, and various solvents.
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metabolism of lipophilic toxicants to hydrophilic metabolites
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toxicant>phase I reactions>primary metabolite> (elimination in urine bile or feces, or) phase II reactions>secondary metabolite>elimination
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phase I reactions of metabolism of lipophilic toxicants (3)
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hydrolysis, reduction, oxidation
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phase II reactions of metabolism of lipophilic toxicants (4)
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glucoronidation, sulfation, methylation, conjugation
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when does hepatotoxicity of chlorinated hydrocarbonds occur
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after phase I metabolism, which results in free radical formation
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why does hepatotoxicity of chlorinated hydrocarbonds occur
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free radicals from phase I metabolism interact with hepatic macromolecules, initiating lipid peroxidation
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centrilobular necrosis (3)
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zone iii necrosis due to CCl4, acetaminophen or ethanol
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clinically significant symptoms of acute toxicity
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jaundice and raised serum transaminase levels
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jaundice
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decreased bile acid synthesis (bilirubin metabolism)
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P450 2E1 drug substrates and carcinogens/toxicants
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ds - acetaminophen. ct - CCl4, ethanol
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what is metabolized in the P450 system? (4)
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testosterone and other steroids, xenobiotics, bile acids
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where is the P450 system located? what's special about it?
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sER of liver. highly inducible by its substrates.
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inducers of P450 (3)
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(substrates) ethanol, barbiturates, St. John's Wort
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St. John's Wort
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induces P450, which can accelerate catabolism of drugs like birth control and HIV therapy, decreasing their therapeutic effect
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t/f everyone's p450 and stuff reacts the same
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false - lots of individual variation
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t/f all drugs cause the same morphological pattern of liver injury
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f - pericentral hepatic injury vs. diffuse hepatitis vs. bile stasis and gall stones
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trichloromethyl free radical
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derived from CCl4
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what does lipid peroxidation cause (2)
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fatty liver and inactivation of mitochondria and enzymes / denaturation of proteins
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why does fat build up in liver? / pathway
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because peroxidation results in no apoproteins in which to escort fat out of liver cells. / lipid peroxidation>membrane damage to rER>polysome detachment>down-regulated apoprotein synthesis>fatty liver
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why does protein denaturation etc. occur in liver in response to lipid peroxidation? (pathway)
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release of lipid products>damage to plasma membrane>^permeability to water calcium and sodium>cell swelling>calcium influx>mito/enzyme deactivation + protein denaturation
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can toxic exposure be prevented?
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yes = requires money
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chronic toxicity of not alcohol causes
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liver cancer. acute = necrosis, ethanol>cirrhosis
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useful applications of ethanol (4)
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versatile solvent, antiseptic, medicines/food flavoring, motor fuel
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consequences of ethanol abuse
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brain/muscle damage, gastritis, pancreatitis, impaired intestinal absorption, testicular atrophy, liver damage
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what types of liver damage occur from ethanol toxicity?
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fatty change (reversible), hepatitis (reversible), cirrhosis (irreversible)
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hepatitis (5)
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liver cell necrosis, inflammation, fatty change in zone 1 (cell periphery). liver tenderness, jaundice.
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cirrhosis causes / clinical signs (5 all together)
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collagen deposition, scar tissue / decreased albumin and clotting factors, jaundice
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cytosolic ethanol metabolism pathway
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90% of normal alcohol metabolism: alcohol dehydrogenase>acetaldehyde (which causes hangovers)
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microsomal ethanol metabolism pathway
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used when drinking in excess: CYP2E1>acetaldehyde. leads to increased TOLERANCE.
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peroxisomal ethanol metabolism pathway
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10% of normal ethanol metabolism: catalase>acetaldehyde
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acetaldehyde>
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acetic acid, via acetaldehyde dehydrogenase
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t/f fatty liver has no clinical symptoms
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true
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biochemical mechanisms of fatty liver synthesis (3)
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1. metabolism via ADH converts NAD to NADH. excess reducing equivalents favors lipid biosynthesis. 2. increased catabolism of fat by peripheral tissues = more FA's delivered to liver. 3. transport problem (duh) - ethanol impairs microtubular function
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t/f fatty liver doesn't look like cloudy swelling
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true - fatty liver has well-defined vacuoles, unlike cloudy swelling (which is hydropic change = water accumulation)
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alcoholic hyaline
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=Mallory bodies; build up in hepatitis
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neutrophils and hepatitis?
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neutrophils around foci of necrosis
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biochemical mechanisms of alcoholic hepatitis (4)
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1. mitochondrial injury, 2. depletion of glutathione, 3. excess generation of ROS by P450 metabolism of ethanol/xenobiotics, 4. protein cross-links induced by acetaldehyde = formation of intracellular mallory bodies
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other than increasing alcohol tolerance, induction of CYP2E1 does what? (4)
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increases metabolism of CCl4, cocaine, acetaminophen, anesthetics
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