Alcohol and Xenobiotic Metabolism Flashcards Preview

DM Biochem > Alcohol and Xenobiotic Metabolism > Flashcards

Flashcards in Alcohol and Xenobiotic Metabolism Deck (26)
Loading flashcards...
1

describe CYP450

  • 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

2

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

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

3

CYP2E1 is specific for _______

CYP2E1 is specific for ethanol metabolism

4

grapfruit juice inactivates ______

grapfruit juice inactivates CYP3A4

5

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

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

6

describe the metabolism of acetaminophen

7

describe the toxicity of high NAPQI levels

8

how does ethanol affect the cerebral cortex?

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

9

describe ethanol uptake and hepatic metabolism

  • 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

10

describe breakdown of ethanol during low levels of ethanol

11

describe alcohol dehydrogenase (ADH)

  • 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

12

how is the toxic metabolite acetaldehyde metabolized?

  • 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

13

describe the reaction that ALDH (acetaldehyde dehydrogenase) catalyzes

14

the liver releases mostly ____ into the blood from acetaldehyde

where is this then used in the body?

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

15

describe ethanol metabolism during high levels of ethanol consumption

16

describe location and function of MEOS

  • 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

describe hereditary deficiency of ALDH-2

  • 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

describe disulfiram aka antabuse

  • 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

describe 2 enzymes ethanol is substrate for

2 enzymes acetaldehyde is substrate for

what happens to products

20

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

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

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

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

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

  • 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

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

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

24

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

25

describe methanol

  • 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

describe ethylene glycol metabolism

  • 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