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23 Cards in this Set
- Front
- Back
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describe basic features of ethanol as a fuel
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-7 kcal/g
-water and lipid soluble (can travel in aq phases and diffuse through membranes) -metabolized mainly in liver via alcohol dehydrogenase and to lesser degree liver microsomal ethanol oxidizing system MEOS; both produce acetaldehyde which is toxic and must be oxidized to acetic acid by acetaldehyde dehydrogenase -excessive ethanol consumption can produce acute abnormal metabolic conditions, usually occurring at same time such as hypoglycemia, ketoacidosis, lacticacidosis -long term effects such as liver disease, acetaldehyde adducts and free radical damage |
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describe other alcohols metabolized
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-methanol can cause blindness and death
-ethylene glycol in antifreeze and brake fluid results in severe acidosis and kidney damage and has a low LD50 (amount that will result in 50% death rate) |
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describe sites of ethanol metabolism
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-<5 in upper GI
-86-98 in liver -2-10 excreted via lungs and kidneys -acetate is transported to other tissues and converted to acetyl CoA |
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describe the enzymes and locations involved in ethanol oxidation
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-cytosolic alcohol dehydrogenase
-mitochondrial acetaldehyde dehydrogenase ALDH2 oxidizes 80% -cytosolic ALDH1 oxides 20% -ALDH1 can produce excessive amounts of NADH leading to hypoglycemia as high levels retard gluconeogenesis |
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describe the different classes of ADH
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-6 classes
-1 is 3% of all liver proteins, 3 isozymes ADH1, 2, 3 all with different specificities -all have high affinities for ethanol (low Km) -ADH2*2 (variant of ADH2) has increased activity (Km inc 260 fold and Vmax dec 10 fold) and produces acetaldehyde too fast such that ALDH cannot oxidize acetaldehyde fast enough to acetate- (homozygous) individuals with this allele cannot tolerate ethanol -class 4 ADH expressed mainly in upper GI where relatively high concentrations of ethanol can exist upon drinking; relative lack of ALDH can lead to acetaldehyde accumulation- may contribute to GI cancer (esophageal an stomach) as seen in heavy drinking -excessive acetaldehyde causes nausea and vomiting |
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describe a drug that inhibits ALDH
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-disulfiram (antabuse) is inhibitor of ALDH and is given for avoidance therapy
-ingestion of ethanol by pt on this drug will generate excess acetaldehyde and nausea and vomiting ensue -not very effective and interferes with other common drugs such as warfarin (anticoagulant) |
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describe fate of acetate
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-acetate (acetic acid) is activated to acetyl CoA and used as fuel in tissues
-acetate to acetyl coA via acetyl CoA synthetase requires CoASH and ATP and yields AMP and PPi which hydrolyzation of drives rxn -first acetic acid is adenylated (linked to AMP) -yields high energy thioester -same rxn to activate FA but enzyme is fatty acyl COA synthetase -food acetate activated same way (vinegar- acetic acid and water) -acetyl CoA used in TCA, FA synthesis, ketogenesis, and some AA |
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describe microsomal ethanol oxidation system
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-oxidizes ethanol to acetaldehyde mainly in liver in endoplasmic reticulum
-uses NADPH and O2 to yield NADP+ and 2H2O -cytochrome P450 enzyme CYP2E1 -CYP2EI is induced in those who drink heavily so that its activity is inc up to 10 fold -has higher Km for ethanol (11mM vs .05-4 mM) therefore oxidizes ethanol only at high concentrations -may produce acetaldehyde too fast and ALDH cannot oxidize it fast enough eventually may lead to liver damage as well as other tissues- glycation with glucose (forming AGE products and denaturing proteins) and adduct formation with malondialdehyde (in degradation of lipid membranes) -cytochrome p450 enzymes generate free radicals and can cause hepatic damage and cirrhosis -CYP2E1 is involved in conversion of acetaminophen to NAPQ1 which is unstable and destructive and requires glutathione to be converted to mercaptopuric acid for excretion. CYP2E1 induction can rapidly convert acetaminophen to NAPQ1 |
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describe phenobarbital and ethanol
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-phenobarbital is barbiturate and anticonvulsant (antiepileptic)
-phenobarbital induces CYP2B1 and CYP2B2 which metabolize it to its inactive component -ethanol inhibits CYP2B1 and CYP2B2 and phenobarbital may reach toxic levels -induction of CYP2B1,2 is why patients require inc amounts of drug with long-term use |
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describe energy production from ethanol
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-cytosolic NADH yields 2.5 ATP in malate shuttle or 1.5 via glycerol 3 phosphate shuttle
-mitochondrial NADH via ALDH yields 2.5 ATP therefore ethanol to acetate = 5 P - -2 from PPi cleavage -acetyl CoA (TCA and ETC) = 10 P bonds -net via malate shuttle is 13 P per mole of ethanol |
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describe maximum energy yield of ethanol
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-via MEOS
-energy consumed by CYP21 (NADPH) = -2.5 -acetaldehyde to acetate = 2.5 -acetyl CoA (TCA and ETC) = 10 net = 8 -NADPH is required to regenerate reduced glutathione, imp in removing H2O2 -NADPH required also in bilirubin reducatase in free radical defense |
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describe empty calories and alcoholism and vitamin deficiency
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-food item that contains metabolic energy but little or no vitamins and other essential nutrients such as essential AA, FA, minerals and antioxidants
-eg distilled spirits- whiskey, gin, vodka -processed foods high in raw sugar, white flour, shortening -beer and wine contain vitamins and other essential nutrients -alcoholics may develop nutritional deficiency due to poor diet (alcohol suppresses appetite) and interference of alcohol with digestion, absorption, storage and distribution and utilization of nutrients -excessive alcohol consumption damages cells lining stomach and small intestine and limits nutrient absorption -chronic alcoholism damages liver and limits its ability to store and distribute nutrients -excessive alcohol consumption affects absorption of most vitamins, with thiamine (B1), riboflavin (B2), pyridoxine (B6), ascorbic acid and folic acid -alcohol related thiamine deficiency is commonly associated with Wernicke's encephalopathy and Korsakoff's psychosis (beriberi) |
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describe thiamine function and deficiency in alcoholism
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-thiamine pyrophosphate TPP is active form of thiamine
-TPP is cofactor for pyruvate dehydrogenase complex in glucose metabolism (pyruvate + NAD +COA = acetyl CoA +CO2 +NADH) -a-ketoglutarate dehydrogenase complex in TCA (a-ketoglutarate + NAD +COA = succinyl CoA +CO2 + NADH) -branched chain a-ketoacid dehydrogenase- degradation of branched-chain AA (valine, isoleucine and leucine) (a-ketoisovalerate +NAD +COA = isobutyryl Coa +NADH + H + CO2) -transketolase- pentose phosphate pathway |
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describe reversible metabolic effects of ethanol
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-inhibition of FA oxidation
-stimulation of TAG synthesis -fatty liver -ketoacidosis -lactic acidosis -hypoglycemia |
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describe irreversible effects of ethanol
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-acetaldehyde and its adducts
-free radicals -inflamed liver with cell death -disrupted blood flow -cirrhosis -loss of liver function -hepatic failure |
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describe ethanol toxicity
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-alcohol induced cirrhosis in 9% of all autopsies performed
-peak incidence at ages 40-55 -3 forms- fatty liver, hepatitis, cirrhosis |
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describe the acute effects of ethanol on fuel metabolism in liver
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-many affects are due to inc in NADH/NAD ration and virtually all of NADH produced by ADH and ALDH
-ratio inhibits FA oxidation as it requires NAD+ -if carbohydrates are consumed, glucose to DHAP to G3P, G3P + FACoA = TAG in adipose tissues. accumulation of fat in liver leads to fatty steatosis. excess TAG can also be exported out of liver as VLDL but excessive levels can lead to hyperlipidemia -NADH can be used in TCA, high NADH/NAD+ ratio inhibits acetyl CoA oxidation via TCA -if drink but do not eat carbohydrates are not consumed- short of glucose so gluconeogenesis and ketogenesis occurs, acetyl CoA is used to generate ketone bodies for fuel; excessive build up can lead to ketoacidosis -high NADH/NAD+ ratio leads to reduction of pyruvate to lactate and prevents reverse rxn leading to lactic acidosis; lactate to pyruvate requires NAD+; build up of lactate dec excretion of uric acid (from purine breakdown) by kidneys and can lead to gout -high NADH prevents formation of pyruvate from glucogenic compounds such as alanine and lactate leading to hypoglycemia; glutamate to a-ketoglutarate requires NAD+ and a-ketoglutarate required to take alanine to pyruvate |
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describe development of alcohol-induced hepatitis
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-acetaldehyde forms adducts with proteins and microtubules and prevents protein secretion from liver
-acetaldehyde binds to reduced glutathione and limits availability of glutathione for radical clearance -induction of MEOS inc formation of free radicals leading to lipid peroxidation -ROS damages mitochondria and inhibits ETC, dec formation of NAD+ limits rate of acetaldehyde oxidation leading to more acetaldehyde accumulating -microtubule damage limits export of VLDL from liver -cellular damage (as inc protein concentration in liver cells, inc osmotic pressure and liver cells swell and can burst) leads to release of hepatic enzymes alanine aminotransferase and aspartate aminotransferase -note in liver damage, if denatured proteins cannot be secreted, swelling can lead to portal hypertension resulting with concomitant formation of esophageal verices in which people can bleed to death just from eating |
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describe ethanol and free radical
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-CYP2E1 is main source of single electrons for free radical formation, leaks single electrons from FMN and heme it contains
-can produce hydroxyethyl radical (CH3CH2O.) as well as other free radicals such as superoxide -main target of free radicals is membrane lipids -inner mitochondrial membrane is critical to ATP synthesis and it may be uncoupled as a result of lipid peroxidation and loss of ATP synthesis -loss of energy production would lead to cell death and chronic inflammation |
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describe cardiomyopathy
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-acetaldehyde adducts and malondialdehyde adducts and aggregates affect other tissues
-heart enzymes and proteins are also affected by adduct formation and cardiomyopathy may result where teh heart becomes weaker and may eventually fail -critical to this is the impaired energy production by damaged mitochondria |
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describe metabolism of other alcohols
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-ADH and ALDH lack specificity with regard to most alcohols
-methanol oxidation produces formaldehyde and formic acid -ethylene glycol is oxidized to oxalic acid (strong acid)- toxic due to adducts; can result in uncontrollable acidemia and it can also be deposited in kidney as calcium oxalate crystals resulting in severe kidney damage |
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describe drugs for alcohol poisoning
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-emergency treatment is ethanol; it will compete for ADH so more toxic aldehydes from methanol and ethylene glycol are minimally produced and parent alcohol is excreted
-antizol- 4MP fomepizole is an inhibitor of ADH and can be used for ethanol overdose as well |
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describe role of oxalic acid
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-some people are susceptible to kidney stones made of oxalate and need to avoid foods high in oxalate such as beets, spinach, peanut butter
-calcium oxalate can precipitate in kidneys; formation of it can make calcium unavailable from some foods -about 60% not absorbed, green leafy veggies have high calcium but also oxalate allowing adequate calcium intake |
