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