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DM Biochem > Alcohol and Xenobiotic Metabolism > Flashcards

Alcohol and Xenobiotic Metabolism Flashcards

1
Q

describe CYP450

A
  • heme containing enzyme that acts as a monooxygenase and forms a hydroxyl group
  • cytochrome P450 reductase provides NADPH for the reaction catalyzed by cytochrome P450
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2
Q

CYP3A4 represents about _____ of CYP450 in the liver and acts on ________ of therapeutic drugs

A

CYP3A4 represents about one third of CYP450 in the liver and acts on more than half of therapeutic drugs

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3
Q

CYP2E1 is specific for _______

A

CYP2E1 is specific for ethanol metabolism

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4
Q

grapfruit juice inactivates ______

A

grapfruit juice inactivates CYP3A4

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5
Q

stimulation of CYP synthesis by ______ can increase the inactivation of other drugs

A

stimulation of CYP synthesis by phenobarbitol can increase the inactivation of other drugs

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6
Q

describe the metabolism of acetaminophen

A
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7
Q

describe the toxicity of high NAPQI levels

A
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8
Q

how does ethanol affect the cerebral cortex?

A
  • ethanol acts on the cerebral cortex and enhances the activity of GABA receptors and lead to relaxation
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9
Q

describe ethanol uptake and hepatic metabolism

A
  • ethanol is readily absorbed from the intestine by passive diffusion
  • the uptake into the blood is very efficient on an empty stomach (~70%)
  • >90% of the ingested ethanol enters the blood and is mostly metabolized by the liver
  • hepatocytes oxidize ethanol in 2 steps:
    1. first to acetaldehyde
    2. then to acetate which is mostly released into the blood
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10
Q

describe breakdown of ethanol during low levels of ethanol

A
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11
Q

describe alcohol dehydrogenase (ADH)

A
  • at low hepatic alcohol levels:
    • ethanol is the main substrate for ADH (80%)
  • ADH uses NAD+ and forms NADH and acetaldehyde
  • hepatic ADH has a high affinity for ethanol
  • ADH has many isozymes with large hereditary variances; ethanol metabolism varies from person to person
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12
Q

how is the toxic metabolite acetaldehyde metabolized?

A
  • acetaldehyde is a substrate for acetaldehyde DH (ALDH) which uses NAD+ to form NADH and the non-toxic acetate
  • hepatic ALDH is found in cytosol and mt
    • mt ALDH-2 has a high affinity and catalyzes >80% of the hepatic acetaldehyde oxidation
    • cytosolic ALDH-1 has a low affinity and acts mainly when cytosolic acetaldehyde accumulates
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13
Q

describe the reaction that ALDH (acetaldehyde dehydrogenase) catalyzes

A
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14
Q

the liver releases mostly ____ into the blood from acetaldehyde

where is this then used in the body?

A

the liver releases mostly acetate into the blood from acetaldehyde

skeletal muscle and heart use the acetate from hepatic ethanol metabolism for their TCA cycle and energy metabolism

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15
Q

describe ethanol metabolism during high levels of ethanol consumption

A
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16
Q

describe location and function of MEOS

A
  • is bound in the ER membrane
  • uses ethanol and NADPH to form acetaldehyde in cytosol
  • has a lower ethanol affinity than alcohol dehydrogenase
  • MEOS activity increases at high ethanol intake especially during chronic alcohol consumption where MEOS is induced by ethanol
    • the rxn catalyzed by CYP450 generates radicals
17
Q

describe hereditary deficiency of ALDH-2

A
  • mt acetaldehyde dehydrogenase has a Km of .2 microM
  • a common allelic variant of ALDH2 is found in East Asian pop. and leads to decreased metabolism of acetaldehyde in mt
  • the mutation increases the Km and decreases the Vmax which leads to high levels of acetaldehyde even at low ethanol intake (Asian flush)
  • acetaldehyde that is released into the blood leads to flushing and elevated heart rate
    • high levels of acetaldehyde results in the clinical feature of nausea and vomiting
18
Q

describe disulfiram aka antabuse

A
  • disulfiram inhibits aldehyde dehydrogenase (acetaldehyde dehydrogenase)
  • ingestion of ethanol leads to 5-10 times higher acetaldehyde levels when a patient takes disulfiram
  • alcohol (small quantity) leads to: flushing, nausea, hangover
19
Q

describe 2 enzymes ethanol is substrate for

2 enzymes acetaldehyde is substrate for

what happens to products

A
20
Q

describe impact of high (cytosolic) NADH/NAD+ ratio

A

reduces gluconeogenesis since substrates provided by the blood cannot be used as normal

  • lactate cannot be used to form pyruvate and stays in the blood
  • alanine cannot be used as it forms pyruvate which is lost as lactate into the blood
  • glutamine cannot be used as less oxaloacetate as substrate for PEPCK is formed from malate in cytosol
  • glycerol cannot be used to form DHAP from glycerol 3-P in cytosol
21
Q

high levels of cytosolic NADH leads to reduced gluconeogenesis and increased ______

A

high levels of cytosolic NADH leads to reduced gluconeogenesis and increased TAG synthesis

The TAGs are released into the blood inside of VLDL which can lead to hypertriacylglycerolemia

22
Q

explain how high levels of mitochondrial NADH leads to ketone body synthesis

A
  • the alcohol-induced mild hypoglycemia leads to release of fatty acids from cells
    • the fatty acids are used for TAG synthesis or are transported into mt
      • high NADH leads to ketone body synthesis
23
Q

acetaldehyde damages _____ which lead to lipid and protein accumulation in hepatocytes

A

acetaldehyde damages tubulins which lead to lipid and protein accumulation in hepatocytes

24
Q

describe the metabolism of other alcohols (methanol, ethylene glycol)

A
25
Q

describe methanol

A
  • found in some alcoholic drinks and is oxidized by alcohol dehydrogenase to the highly toxic formaldehyde inside the cells of: liver, neurons and retina
    • together w/ formic acid, it leads to mental disturbance and blindness
  • alcohol dehydrogenase has a higher affinity for ethanol (or competitive drugs) than for methanol
    • ethanol or fomepizole can be used as comp. inhibitors
26
Q

describe ethylene glycol metabolism

A
  • ethylene glycol (often found in antifreeze) tastes sweet and if untreated can lead to formation of calcium oxalate in the kidneys –> kidney failure –> death in a few days
  • the immediate treatment can include:
    • inhibition of alcohol dehydrogenase
    • empyting of stomach
    • treatment of acidosis
    • admission to ICU and put on respirator

DM Biochem (33 decks)

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