Term
| the major pathways of acetaminophen metabolism are (2) / children vs. adults |
|
Definition
| glucuronidation and sulfation / children are mainly sulfation, adolescents/adults are mainly glu |
|
|
Term
| if CYP2E1 activity is induced, acetaminophen metabolism is shifted to / which does what |
|
Definition
| P450 system that generates a highly reactive intermediate that binds to and depletes GSH. people with decreased GSH are more susceptible to acetaminophen toxicity |
|
|
Term
| how do you get decreased stores of GSH (2) |
|
Definition
| fasting (kids who don't feel well don't eat), chronic alcoholism |
|
|
Term
| hepatotoxicity of acetaminophen / pathology / treatment |
|
Definition
| 2-4 days after ingestion / centrilobular necrosis / n-acetylcysteine (is swallowed and converted to cysteine, which replenishes GSH stores and also detoxifies the acetaminophen reactive intermediate) |
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|
Term
| children are _ susceptible to acetaminophen toxicity. _ margin of safety between therapeutic and toxic |
|
Definition
|
|
Term
| most common reason for liver transplantation in the US |
|
Definition
|
|
Term
|
Definition
| (acetylsalicylic acid) knocks out urea cycle > cerebral edema > coma (Reye syndrome) |
|
|
Term
|
Definition
| (aspirin) toxic to mito, especially in children w/ fever because of the release of cytokines |
|
|
Term
|
Definition
| ATP depletion / decreased FA oxidation > microvesicular fatty change (Reye syndrome) |
|
|
Term
|
Definition
| mainly on CNS - depressant, directly affecting membrane fluidity |
|
|
Term
| chronic effects of ethanol are mediated by several mechanisms (4) |
|
Definition
| 1. direct toxicity of alcohola nd its metabolites: acetaldehyde can induce lipid peroxidation and form protein adducts. 2. free radicals as by-prodcuts during metabolism by p450 3. excess use of ethanol can displace consumption of other nutrients and vitamins - this is important in the chronic neurologic effects of ethanol. 4. induction of p450 induces metabolism of drugs and chemicals to toxic intermediates |
|
|
Term
| alcoholic cirrhosis / accompanied by (4) |
|
Definition
| irreversible. micronodular (fibrosis in between regenerating aggregates of hepatocytes) w/ fatty change. / muscle wasting, weakness, ascites, tendency for massive GI hemorrhage (because clotting factors are low) |
|
|
Term
| potential mechanism for fibrous scarring in liver damage |
|
Definition
| conversion of stellate cells (mesenchymal cells filled with lipid in the space of Disse) to fibroblasts |
|
|
Term
| stimulation of collagen synthesis in liver may be caused by |
|
Definition
| the same mediators of peptide growth factors responsible for fibrous scar formation in a healing wound |
|
|
Term
| chronic alcoholics are highly susceptible to _-induced liver injury at _ doses |
|
Definition
| acetaminophen / therapeutic |
|
|
Term
| difference between hypoxia and ischemia |
|
Definition
| ischemia prevents nutrients as well as oxygen from getting to tissues |
|
|
Term
| biochemical lesions in ischemia are (3) |
|
Definition
| ATP depletion, mitochondrial damage, plasma membrane damage (overloading of calcium) |
|
|
Term
| time it takes to kill a heart/brain cell |
|
Definition
| heart - 20-30 minutes no O2; brain - 2-3 minutes |
|
|
Term
| leading cause of death in developed countries |
|
Definition
|
|
Term
| biochemical events in ischemia |
|
Definition
| decreased oxidative phosphorylation in mito leads to less ATP, which leads to inactive sodium pump, increased anaerobic glycolysis and detachment of ribosomes |
|
|
Term
| consequences of inactive sodium pump |
|
Definition
| influx of calcium, water and sodium (and efflux of potassium) leads to ER swelling, cellular swelling, and loss of microvilli blebs |
|
|
Term
| consequences of increased anaerobic glycolysis |
|
Definition
| decreased glycogen. increased lactic acid = decreased pH = clumping of nuclear chromatin |
|
|
Term
| consequences of detachment of ribosomes |
|
Definition
| decreased protein synthesis |
|
|
Term
| ATP is synthesized as a result of |
|
Definition
| oxidative phosphorylation of ADP in the mitochondrial membrane |
|
|
Term
| ATP can also be synthesized by |
|
Definition
| the Embden-Meyerhof glycolytic pathway in the cytoplasm |
|
|
Term
| what happens biochemically in ischemia to stop ATP production |
|
Definition
| cytochrome C can't convert oxygen to water because there is no oxygen; complex V (ATP synthase) is never reached |
|
|
Term
| cyt C causes apoptosis (instead of ischemic necrosis) by activating Apaf-1 IF |
|
Definition
| there's OMM damage AND ATP is still being made |
|
|
Term
| mitochondria dysfunction and membrane damage in ischemia |
|
Definition
| decreased phospholipid synthesis/recycling = phospholipid degradation and loss to lipid breakdown products. increased cytosolic calcium activates phospholipases which also break down PLs, and activates proteases which damage the cytoskeleton |
|
|
Term
| increased cytosolic calcium activates / resulting in |
|
Definition
| phospholipase A2 / degradation of membrane phospholipids |
|
|
Term
| oxidative mitochondrial damage > |
|
Definition
| mitochondrial permeability transition |
|
|
Term
|
Definition
| accompanied by phospholipid damage. induces loss of permeability barrier and massive calcium influx and calcium precipitates |
|
|
Term
| free radical attack on membrane |
|
Definition
|
|
Term
| activation of phospholipases > |
|
Definition
| detergent effect of FFA; loss of permeability barrier to calcium |
|
|
Term
| see p. 41,42,44 in this lecture |
|
Definition
|
|
Term
| coagulation necrosis / influx of |
|
Definition
| = ischemic damage (coagulation in vessels causes necrosis) / neutrophils |
|
|
Term
| effect of decreased ATP on proteins |
|
Definition
| denatures them; loss of intracellular amino acids leads to cell membrane damage |
|
|
Term
| extensive necrosis in heart can cause _ which does what? |
|
Definition
| shock, which causes lack of myocardial motility in the healthy cells left |
|
|
Term
| 3-5 days after myocardial infarct |
|
Definition
| neutrophils. nuclei of myocardial cells are lysing so the membranes are fuzzy |
|
|
Term
| these 3 enzymes are used as clinical markers for myocardial infarction (because they are released when cells lyse) / time frames |
|
Definition
| creatine kinase (starts 2-4hrs, peaks 24-48hrs, disappears by 72 hours), lactate dehydrogenase (after creatine kinase), troponins (starts 2-4hrs, remain elevated 7-10days) |
|
|
Term
| reperfusion injury is mediated by (3) |
|
Definition
| influx of neutrophils in blood, generation of ROS, and apoptosis of myocardial cells surrounding the necrotic cells damaged by ischemia |
|
|
Term
| internal oxidation from _ and external oxidation from _ may be enough to induce _ where? |
|
Definition
| mitochondria, neutrophils, apoptosis at periphery of ischemic injury |
|
|
Term
| what type of tissue is fibrosis |
|
Definition
| collagen type 1 scar tissue. fills in holes where dead tissue was |
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