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MCP Unit 6 > Alcohol Metabolism > Flashcards

Alcohol Metabolism Flashcards

1
Q

overview

A
  • ethanol that we consume is converted to acetate in the liver and generates NADH
  • two step process-ethanol to acetaldehyde tjem tp acetate
  • alcohol dehydrogenase and acetaldehyde dehydrogenase
  • ADH in cytosol and ADLH in mito
  • most of the acetate enters blood and travels to muscle and its converted to acetyl coA and enters TCA
  • 10-20% oxidized though MEOS comprised of cytochrome P450 (primarily CYP2E1)
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2
Q

ADH and ALDH

A
  • ethanol is a small molecule which has solubility in water and lipids
  • absorbed from intestine by passive diffusion
  • small (0-5%) enters gastric mucosal cells in the upper GI tract where it is metabolized
  • remainder enters blood where 85-98% metabolized in liver and 2-10% excreted in lungs or kidneys
  • primary route through ADH in cytosol, makes NADH
  • if acetaldehyde isn’t further degraded can cause harm to other tissues
  • ~90% of acetaldehyde formed is further metabolize by a low Km ALDH which takes it to acetate and makes more NADH
  • acetate is non-toxic and can enter Krebs cycle or pathway for FA synthesis once converted to acetyl coa
  • most acetate enters blood and is converted in muscle and other tissues
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3
Q

MEOS

A

-other route for alcohol metabolism
-in ER
-primary Cyt P450 is CYP2E1
-converts ethanol to acetaldehyde using NADPH and oxygen (e acceptor)
10-20% of ethanol oxidation in a moderate drinker

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4
Q

ADH isozymes

A
  • differ in specificity of chain length of the alcohol substrate
  • at high concentrations ethanol can be metabolized by many members of ADH family
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5
Q

ADH1

A
  • highest affinity
  • three genes that exist has allelic variants
  • can form homodimers and heterodimers with each other, but not with other families
  • very high quantity in the liver (3% of soluble protein)-liver ADH
  • highest affinity, liver is major site of ethanol metabolism
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6
Q

ADH4

A
  • upper GI tract
  • at high ethanol concentration in the upper GI
  • conversion in upper GI to acetaldehyde might contribute to risk of cancer for heavy drinkers
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7
Q

ADH2

A

liver and lower GI tract

Km 23

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8
Q

ADH3

A
  • present in many tissues
  • inactive toward ethanol
  • active toward long chain alcohols
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9
Q

acetaldehyde dehydrogenase

A
  • acetaldehyde to acetate
  • makes NADH
  • > 80% of acetaldehyde oxidation in liver catalyzed by ALDH2
  • km of 0.2 micrometers- very low Km, very high affinity
  • other acetaldehyde oxidation by ALDH1 (cytoplasm)
  • both are tetramers, subunits have 499-500 aa
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10
Q

inactive ALDH2

A
  • causes flushing, nausea, vomiting, distaste for alcoholic beverages
  • single aa sub of glu to lys leads to allelic variant ALDH2*2 which has a 23x higher Km and 35x lower vmax (only works at high concentrations)
  • homozygosity for this allele provides protection about alcoholism
  • alcoholics treated with ALDH inhibitors which help them abstain, but makes damage much worse if they do drink
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11
Q

acetyl coa synthetase

A
  • required for acetate to acetyl CoA
  • liver primary isoform is ACS I, cytosolic
  • generates acetyl CoA for cholesterol and FA syn
  • acetate entry regulated by cholesterol and insulin, most acetate enters the blood
  • taken up by other tissues which have a high concentration of ACS II (mito)
  • the acetyl CoA generated can enter TCA and be oxidized to CO2
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12
Q

cytochrome P450

A
  • ethanol is also oxidized in liver by MEOS (ER cyt p450 enzymes)
  • ethanol and NADPH donate electrons which reduces oxygen to 2 waters
  • cyt p450 superfamily have two major catalytic components
    1. cytochrome p450 reductase which transfers electrons via FAD and FMN from NADPH
    2. cytochrome p45- which contains binding sites for oxygen and substrate and carriers out the reaction

**reductase transfers electrons and cytochrome holds substrates

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13
Q

CYP2E1

A
  • 1 of over 100 cyt p450 mixed function oxidases
  • 2 is gene family, E is subfamily, 1 is enzyme
  • highest activity when ethanol is substrate but other p450s are also involved
  • MEOS is ethanol oxidizing activity of all P450
  • CYP2E1 has much higher km for ethanol than ADH1- more involved when large quantities are improved
  • products from CYP2E1 are acetaldehyde and ROS
  • chronic consumption increases expression, acts via stabilization of protein and protection against degradation
  • increases ethanol clearance but produces acetaldehyde faster than it can be removed- damage to liver and other tissues
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14
Q

variations in ethanol metabolism

A

-varies among people
-determines alcoholism, alcohol induced liver disease, other diseases linked to liver disease
Factors:
genotypes-different polymorphic forms of ADH/ALDH can affect oxidation and acetaldehyde accumulation
-different variants of CYP2E1 can vary activity 20 fold
-drinking history: gastric ADH decreases and CYP2E1 increases with amount of alcohol consumed
-women affected more- lower gastric ADH, 12% smaller water space
-quantity consumed

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15
Q

acute effects on lipid metabolism

A
  • inhibition of FA oxidation and stimulation of TAG synthesis leading to a fatty liver
  • ketoacidosis or lactic acidosis causing hyper or hypoglycemia
  • reversible
  • in contrast, acetaldehyde and ROS can lead to hepatitis-liver inflammation and necrotic cell death
  • damage to hepatocytes leafing to cirrhosis characterized by fibrosis, altered blood flow, and loss of liver function
  • acute effects from NADH:NAD ratio increasing
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16
Q

mechanisms of acute effects on lipid metabolism in liver

A
  1. ethanol oxidation by ADH and ALDH increases NADH:NAD ratio
  2. high ratio inhibits FA oxidation and TCA cycle and leads to accumulation of free FA
  3. FA are re-esterified to glycerol-3-phosphate by acyltransferases in the ER (alcohol induces acyltransferases). increased TAGs are converted to VLDL which accumulate in the liver and enter the blood and lead to fatty liver and ethanol induced lipidemia
  4. FA that are oxidized are converted to acetyl CoA and then to ketone bodies
  5. inhibition of the TCA cycle causes acetyl CoA to enter the ketone body pathway and raises their levels
  6. high ratio increases production of lactate by lactate dehydrogenase
  7. incraese in blood lactate decreases uric acid excretion by the kidney (gout pts not advised to drink)
  8. more lactate, less pyruvate, no gluconeogenesis- drinking in fasting state causes hypoglycemia
    - with a meal causes transient hyperglycemia because ratio inhibits GAP dehydrogenase
17
Q

effects of chronic alcohol consumption

A
  • increased acetaldehyde and ROS in liver which are released into the blood
  • forms adducts with aa and sulfhydryl groups within aa and proteins, also with nts and phospholipids
  • adduct formation causes decrease in protein synthesis
  • this accumulation of proteins causes water to enter into hepatocytes-swelling liver and portal hypertension
  • disrupts hepatic architecture
  • cell damage releases hepatic enzymes like ALT and AST
18
Q

effects of chronic consumption 2

A
  • acetaldehyde forms an adduct with GSH and various antioxidant enzymes so they can’t deal with ROS-damage to proteins, lipids, nucleotides
  • induction of MEOS increases ROS production, lipid peroxidation and cell damage
  • peroxidation of lipids in mito inner membrane and oxidative damage to proteins inhibits ETC and diminishes acetaldehyde conversion to acetate
  • adduct formation with proteins can cause loss of function
  • adduct formation with tubulin causes decreased secretion of plasma proteins and VLDL from liver
  • proteins normally in blood accumulate in the liver
19
Q

fibrosis

A
  • insult to the liver causes a wound healing reaction
  • causes overproduction of extracellular matrix which progresses to sclerosis which involved degeneration of the components of the extracellular matrix
  • about 20% of heavy drinkers progress from fibrosis to cirrhosis
20
Q

hepatic cirrhosis

A
  • damage is irreversible
  • initially liver is enlarged, full of fat and crossed with collagen fibers and have nodules of ballooning hepatocytes between the liver
  • as function decreases, liver becomes shrunken
  • loss of metabolic functions include protein synthesis and secretion, detoxification pathways, ability to incorporate amino groups into urea
  • toxic levels of ammonia
  • diminished conjugation and secretion of bilirubin occurs with increased accumulation of bilirubin in the blood
  • increased blood bilirubin causes jaundice
21
Q

alcohol related diseases

A
  • obesity is environmental and genetic, ethanol is caloric
  • alcoholism is both, addiction, damage of internal organs
  • jaundice is environmental-can’t conjugate bilirubin
  • liver fibrosis is environmental-damage to liver- collagen secretion and loss of function

MCP Unit 6 (9 decks)

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