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85 Cards in this Set
- Front
- Back
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What is hypertrophy?
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-increase in cell size but not cell number
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What is hyperplasia?
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-increase in cell number but not cell size
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What is atrophy?
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-decrease in cell size but not cell number
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What is the most vulnerable intracellular systems?
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-cell membrane integrity
-aerobic respiration -enzymatic and structual proteins -integrity of genetic materal |
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What are the mechanisms of cell injury?
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-precise biochemical site of action is not always known
-one locus (site of action leads to wa wide range of secondary effects -biochemical change leads to morphologic change -type of injury, duration, and severity leads to outcome -consequences of cell injury depend on cell type and state -susceptibility is proportional to basal cell metabolism, fuel supply, and adaptive responses |
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What cell types have high susceptibility? time frame?
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-neurons
-3-5 min |
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What cell types have intermediate susceptibility? time frame?
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-myocardium, hepatocytes, and renal epithelium
-30 min- 2 hours |
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What cell types have low susceptibility? time frame?
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-fibroblasts, epidermis, skeletal muscle
-many hours |
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What are critical events in irreversible cell injury?
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-inability to reverse mitochondrial dysfunction
-distrubances in membrane function |
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What is a free-radical?
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-chemical species with single unpaired electron in outer orbital
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How are free-radicals fomed?
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-absorption of radiant energy
-reduction-oxidation (redox) reactions -enzymatic metabolism |
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Whata re the targets of free-radicals?
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-lipid peroxidation
-nonperoxidative mitochondrial damage -DNA damage -protein cross-linking |
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What occurs during the pathway of apoptosis of cells?
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-caspase activation inhibition of mRNA translation
-condensation of cell and organelles -chromatin condensation and DNA fragmentation -loss of membrane asymmetry -membrane remains impermeable -cell falls apart into apoptotic bodies |
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What occurs during the pathway of necrosis of cells?
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-pro-inflammatory signaling and cytokine production
-swelling of the cell and organelles -mottled chromatin and condensation -loss of membrane asymmetry -rapid loss of membrane permeability -cell membrane explodes and remains stay together |
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What decreases in concentration that causes cell injury during ischemia? Which leads to?
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-oxygen
-decreased oxidative phosporylation -membrane injury |
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What does decreased oxidative phosporylation lead to after ischemia?
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-decreased ATP
-membrane injury |
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What does decreased ATP during ischemia lead to?
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decreased sodium pump
-increased glycolosys -other effects such as detachment of ribosomes (leads to decreased protein synthesis and then lipid deposition)(reversible) |
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What does decreased sodium pump usage lead to?
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- increased influx of calcium adn water
-increased efflux of potassium -leads to cellular swelling, loss of microvilli, blebs, ER swelling, and myelin figures -reversible |
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What does increased glycolysis lead to during ischemia in a cell?
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-decreased glycogen and decreased pH
-leads to clumping of nuclear chromatin (reversible) -intracellular release of lysosomal enzymes (irreversilbe) -decreased basophilia (decreased RNP) , nuclear changes, adn protein digestion (irreversible) - |
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What does membrane injury lead to during cell ischemia?
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-increasde calcium influx
-leads to increased calcium in mitochondria (irreversible) -increased exit of enzymes (ireversible) |
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What enzyme protects cells from free-radical damage of cell membrane?
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-glutathione peroxidase
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What is the pathway for lipid peroxidation with Glutathione peroxidase?
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-causes membrane damage to RER
-polysome detachment -decreased apoprotein syntheis -becomes fatty liver |
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What is the pathway for lipid peroxidation without glutathione proxidase?
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-release products of peroxidation
-damage to plasma membrane -permeability to sodium, water, abd calcium increased -cell swells -massive influx of calcium -inactivation of organelles and denaturing of protein |
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What is the pathway leading to toxicity?
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-toxicant-->delivery--> interaction with target molecule and alteration of biological environment--> cellular dysfunction and injury (toxicity)--> dysrepair (toxicity)
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What are the factors that facilitate the distribution of toxin to the target?
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-porosity of capillary endothelium
-specilized membrane transport -accumulation in organelles -irreversible binding |
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What are mechanisms that oppose the distrbution of toxin to target?
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-protein binding
-specilized barriers -distribution to storage sites -association with intracellular binding protein -export from cells (PgP)->efflux |
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What is Pb (lead) ions as an ultimate toxicant?
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-parent xenobiotic
-CNS damage in children |
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Why are metals toxic?
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-because they bind to many enzymes
-enzymes stop functioning |
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How is tetrodotoxin a ultimate toxicant?
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-parent xenobiotic
-causes sodium ion blockage in motor neurons -paralysis |
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How is TCDD a ultimate toxicant?
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-parent xenobiotic
-causes cancer |
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How is HCN a ultimate toxicant?
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-parent xenobiotic
-prevents oxidation phosphorylation -don';t get ATP |
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How is CO an ultimate toxicant?
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-parent xenobiotic
-competes wih oxygen -suffocation |
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What is the xenobiotic metabolite of amygdalin as ultimate toxicants?
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-HCN
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What is the xenbiotic metabolite of arsenate as an ultimate toxicant?
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-arsenite
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What is the xenbiotic metabolite of flouroacetate?
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-fourocitrate
-body can't deal with it -causes acidosis, hypocalcema and acute renal failure |
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Wha is the xenobiotic metaboliteof ethlene glycol (antifreeze) as an ultimate toxicant?
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-oxalic acid
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What is the xenbiotic metabolite of hexane as an ultimate toxicant?
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-2-5 hexanedione
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What is the xenbiotic metabolite of acetaminophen as an ultimate toxicant?
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-N-acetyl-p-benzoquinoneimine
-regulated by CYP2E1 by alcohol |
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What is the xenbiotic metabolite of CCl4 as a n ultimate toxicant?
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-CCl3OO.
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What is the xenbiotic metabolite of benzo[a]pyrene (BP)?
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-BP-7,8-diol-9,10-epoxide
-BP-radical cation |
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What are the reactive oxygen and nitrogen species as ultimate toxicants?
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-hydrogen peroxide acts as anti-bactrial and generates reactive oxygen
-diquat,doxorubicin, and nitrofurantoin -Cr(V), Fe(II), Mn(II), Ni(II) (fenton metabolises and becomes oxgen intermediates) -paraquat and peroxynitrite (becomes reactive oxygen and nitrogen intermediates) -hydroxyl radical (most reactive) |
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What are the various endogenous compounds as ultimate toxicants?
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-sulfonamides-->albumin-bound bilirubin--> bilirubin (non-diffusible) (causes jaundice)
-CCl3OO.-->unsaturated fatty acids--> lipid peroxyl radicals, lipid alkoxyl radicals, and 4-hydroxynonenal -HO.-->proteins-->protein carbonyls |
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What are electophiles?
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-molecules containing eletron-deficient atom with partial or full positive charge that allows it to react by sharing electron pairs with electron-rich atoms in nucleophiles
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How are they related to toxication? Detoxication?
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-insertion of oxygen, formation of conjugated double bonds, heterolytic bond cleavage
-glutathione conjugation |
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What is acetaldhyde? What is its parent toxicant? enzyme catalysing toxication? toxic effect?
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-nonionic electrophiles
-ethanol -ADH -hepatic fibrosis |
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What is 2,5 hexane dione? What is its parenttoxicant? enzyme catalysing toxication? toxic effect?
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-nonionic elecrophile
-hexane -p450 -axonopathy |
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What is acrolein? What is its parent toxicant? enzyme catalysing toxication? toxic effect?
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-nonionic elecrophile
-allyl alcohol and allyl amine -ADH and MAO -hepatic necrosis and vascular injury |
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What is DES-4,4'-quinone? What is its parent toxicant? enzyme catalysing toxication? toxic effect?
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-nonionic electrophile
-DES -peroxidases -carcinogenesis |
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What is NAPQI? What is its parent toxicant? enzyme catalysing toxication? toxic effect?
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-nonionic elecrophile
-acetaminophen -P450 and peroxidases -hepatic necrosis |
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What is benzylic carbocation? What is its parent toxicant? enzyme catalysing toxication? toxic effect?
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-cationic electrophile
-benzylic carbocation -7,12-DMBA -P450-->ST -carcinogenisis |
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What is cabonium cation? What is its parent toxicant? enzyme catalysing toxication? toxic effect?
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-cationic electrophile
-DENA -P450-->s.r -carcinogenesis |
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What is mercury (II) ion? What is its parent toxicant? enzyme catalysing toxication? toxic effect?
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-cationic electrophile
-elemental Hg -catalase -brain injury |
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What is Diaquo-diamino platinate (II)? What is its parent toxicant? enzyme catalysing toxication? toxic effect?
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-cationic electrophile
-Cisplatin -s.r. -renal tubular necrosis |
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How do you get rid of parent molcule of free radicals?
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-by removing it by NADPH but not a good idea because still needed for some metabolic processes in the body
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What is the fenton reaction? Significance?
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-takes oxygen from peroxide and makes it ionic for cleavage into water
-in the presence of metals, it generates bad OH -these metals can bind to enzyme and become unreactive and can't participate in reaction |
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How is the fenton reaction a good pathway?
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-metals bind to other molecules by cholation
-for iron--> use deteroxamine -bathocuprome for copper -use scavangers of oxygen such as superoxide dismutase |
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What free radicals are formed by ONOO.?
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-undergoes peroxide fixation-->forming 2 free radicals such as NO2 and CO3
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What happens when gluathione is all consumes durign detox?
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-syntheis rate will be insufficient to keep up with the pace at which toxicity is generated and shifts to toxicity pathway
-with decreased glutathione, compromise the GSH pathway less stable to detoxify |
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What are the various electrohpilenucleeophile combination from softest to hardest?
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-carbon in polarizxed doublebonds--> sulfur in thiols
-carbon in epoxides--> sulfur in methionine -aryl carbonium ions-->nitrogen in primary and secondary group of aminoacids -benzylic carbonium ions, nitrenium ions-->nitrogen in amino groups of purine bases in nuclein acids -alkyl carbonium ions--> oxygen of purines and pyrimidines in nuclein acids and phosphate oxgen in nuclein acids |
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What is the molecular pathway of hydrogen abstraction?
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-fatty acid with 3 double bonds intiates with hydrogen abstration by hydroxyl radical
-molecular rearrangement occurs and becomes conjugated diene -oxygen uptake occurs and becomes pereoxyl radical -progression occurs with a chain reaction of hydrogen abstraction and becomes a lipid hydroperoxide -reaction is terminated (not as toxic as free radical) |
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How does protein repair work?
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-Thiredoxin pathway and glutaredoxin pathway occurs
-as long as enough NADPH is available |
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What is the pathway for DNA repair?
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-DNA has dimer
-dimer recognized by a nuclease at site of damage and is cut -dimer excised -gap filled by DNA polymerase -nick sealed by DNA ligase |
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What are the various factors that attribute with interfering with the delivery of hydrogen to electron transport chain during mitochondrial ATP synthesis?
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-glycolysis (hypoglycemia)
-gluconeogenesis -fatty acid oxidation -pyruvate dehyrdogenase -citrate cycle -depleters of TPP (ethanol) -depleters of coenzyme A -depleters of NADH |
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What are the inhibitors and competitors of electron transport complexes that inhibit transfer of electrons along respiratory chain to oxygen of mitochondrial ATP synthesis?
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-rotenone, MPP+,a nd paraquat inhibit NADH-coenzyme Q reductase (complex I)
-antimycin A inhibits cytochrome Q-cytochrome c reductase (complex II) -cyanide, formate and nitrogen oxide radical inhibits cytochrome oxidase (complex IV) -dinitronaniline and diphenylether herbicides inhibit multiple sites of transfer -CCl4, doxorubicin, menadione, and MPP+ compete as electron acceptors |
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What are the various factors that can interfere with oxygen delivery to terminal electron transporters of mitochondrial ATP synthesis?
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-chemicals causing respiratory paralysis (CNS depressants, convulousent)
-chemicals causing ischemia (cocaine and ergo+alkaloids) -chemicals inhibiting hemoglobin oxygenation (CO) |
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What are the various factors that inhibit activity of ATP synthase during mitochondrial ATP synthesis?
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-ATP synthase (DDT)
-adenine nucleotide translocator -phosphate trasnporter -uncouplers |
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What are various chemicals that can cause mitochondrial DNA damage and impaired transcription during ATP synthesis?
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-antiviral drugs: zidovudine, zalcitabine, didanosine, and fialuridine
-thanol (when chronically consumed) |
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What is the consequance of inhibiting ATP synthesis?
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-constant influx of of Na+
-auumulation in cells causing swelling and eventually lysis |
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What si the significance of intracellular calcium?
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-hides in ER or SR
-to contract, open calcium channels -to build up Ca+, need ATPases -calcium hides in mitochondria -Calcium phosphate can casue kidney stones, which can damage mitochondria |
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How is there increased influx of calcium in cells?
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-alternations of plasma membrane permeability
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How is there decreased efflux of calcium in cells?
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-insufficient ATP for Ca2+/Na+ countertransporter
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Where is calcium stored for release?
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-mitochondria and endoplasmic reticulum
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What are the consequences of elevated Calcium concentrations in cells?
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-mtochondrial membrane deporlarization
-microfiliament dissociation -activation of hydrolytic enzmes |
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What are chemicals inducing calcium influx into the cytoplasm via ligand-gates channels in neurons?
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-glutamate receptor agonists: glutamate, kainite, and domoate
-"capsaicin receptor agonists: capsaicin and resinifertoxin |
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What are chemicals inducing Cacliuym influx into the cytoplasm via voltage gated channels?
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-maitotoxin and hydroxide radical
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What are chemicals inducing calcium influx into the cytoplasm via newly formed pores?
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-maitotoxin, amphotericin B, chlordecone, methylmercury, and alkyltins
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What are chemicals that induce calcium influx into the cytoplasm across disrutped cell membrane?
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-detergents: exogenous detergents, lysophosphilipids, and free fatty acids
-hydrolytic enzymes- phospholipases in snake venoms, and endogenous phospholipase A2 -lipid peroxidation- carbon tetrachloride -cytoskeletal toxins (by inducing membrane blebbing)- cytocholasins and phalloidin |
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What are chemicals inducing calcium influx into the cytoplasm from mitochondria?
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-oxidants of intramitochondrial NADH: alloxan, t-BHP, NAPQI, divicine, fatty acid hydroperoxides, menadione, and MPP+
-others: phenylarsine oxide, gliotoxin, .NO, and ONOO- |
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What are chemicals that induce calcium influx into the cytoplasm from the endoplasmic reticulum?
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-IP3 receptor activators: y-HCH (lindane), IP3 formed during "excitotoxicity"
-ryanodine receptor activators: sigma-HCH |
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What are chemicals that inhibit caclium export from the cytoplasm (inhibtors of calcium ATPase in cell membrane or endoplasmic reticulum)?
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-covalent binders: acetaminophen, bromobenzene, CCl4, chloroform, DCE
-thiol oxidants: cystamine (mixed disulfide formation), diamide, t-BHP, menadione, and diquat others: vanadate and Cd 2+ -chemicals impairing mitochondrial ATP synthesis |
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How does overproduction of RNS and ROS occur in cells?
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-uncoupling of oxidative phosphorylation
-overuse of proteases during detox |
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What is the significance of interactions between ATP, calcium, and ROS/RNS production?
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-everything is in equilibrium
-decrease ATP, decrease ability to excrete calcium, increase intracellular calcium, increase ROS/RNS, -this leads to a decrease in ATP syntheis due to lowered amount of NAD(P)H |
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What is caspase?
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-a protease that has affinity for cysteine aspartate
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What signals occur to cause apoptosis?
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-either by receptor stimulation, mitochondrial insult, or DNA insult
-eventually interacts with cytochrome C from mitochondria, which can be ejected -once ejected, fathers Apaf-1 and PC-g (procaspase g) -PC-g becomes active and eventually an effector caspase -this leads to hydrolysis of specific cellular proteins and apoptosis |
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What signals are necessary for necrosis?
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-Na+ channels become degenerated (influx of Na+)
-this leads to constant influx of calcium from extacellular, endoplasmic reticulum and mitochondria -this leads to calpain activation which causes lysosome rupture -this leads to cathepsin release and eventual cell death |
