Alcohol and Xenobiotic Metabolism of the Liver

Question 1

phases of drug metabolism in the liver

Answer 1

phase I: hydroxylation by microsomal CYP450

phase II: conjugation using UDP glucuronic acid, PAPs (sulfate), Glutathione, AA

Question 2

where do the phases of drug metabolism occur

Answer 2

phase I is in the ER and phase II in they cytosol

Question 3

reason why we detoxify alcohol/xenobiotics

Answer 3

to increase their water solubility (for excretion) in the two phases

Question 4

do all drugs go through both phases

Answer 4

No some skip phase I hence not using CYP450

Question 5

what does CYP450 do to drugs

Answer 5

can inactivate it, make it more polar to be excreted, activate it, convert it to a toxic metabolite

Question 6

what does CYP3A4 rep/do

Answer 6

1/3 of CYP450 and acts on more than half of the therapeutic drugs like statin and tamoxifen

Question 7

what does CYP2E1 do

Answer 7

ethanol metabolism

Question 8

what does CYP450 contain

Answer 8

heme containing enzyme —-induced by drugs and ethanol

Question 9

provides CYP450 the NADPH it needs to catalyze its reaction

Answer 9

CYP450 reductase

Question 10

what induces CYP450

Answer 10

increase transcription of mRNA of CYP450, drugs like phenobarbitol, ethanol consumption (specifically activates the CYP2E1 –part of microsomal ethanol oxidizing system MEOS)

Question 11

what patients do you avoid giving phenobarbitol to

Answer 11

those with acute intermittent porphyria —if you stimulate heme synthesis in them leads to higher ALA (similar to GABA hence cell death)

Question 12

grapefruit juice can inactive which cytochrome

Answer 12

CYP3A4

Question 13

what happens then when CYP3A4 has been inactivated

Answer 13

drugs like statin and tamoxifen would be less inactive

Question 14

why must one increase the amount of warfarin intake if drug is taken together with phenobarbital

Answer 14

phenobarbital degrades warfarin so more must be taken to overcome

Question 15

what happens if taken high warfarin with phenobaribital then one stops taken phenobarbital but continues high dose of warfarin

Answer 15

warfarin level too high hence dangerous bleeding can occur

Question 16

what happens with acetaminophen (tylenol) in the body of chronic alcoholics

Answer 16

it is more processed by CYP2E1 and leads to toxic compound NAPQI

Question 17

fate of NAPQI

Answer 17

can be detoxified by glutathione then excreted in urine or can lead to cell death (REAL BAD!!!)

usually leads to cell death if just too much NAPQI and empty stomach in comparison to the glutathione present

Question 18

how do you treat acetaminophen poisoning

Answer 18

with drug acetadote – has N acetyl cysteine that binds directly to NAPQI and provides cysteine for glutathione synthesis

Question 19

main cells to metabolizes most of blood ethanol to acetaldehyde

Answer 19

hepatocytes

Question 20

enzymes that form acetaldehyde from ethanol

Answer 20

alcohol DH (low Km) and MEOS CYP2E1 (high Km)

Question 21

why do asians tend get drunk a lot quicker than most

Answer 21

they only have ALDH-1 (acetylaldehyde DH-1) and a less active ALDH-2 so acetaldehyde builds in cytosol –> eventually turned to acetate using ALDH-1 before being released into blood

Question 22

fate of acetaldehyde in blood

Answer 22

can be taken up into mito and using ALDH-2 turned into acetate or in the cytosol, using ALDH-1 can be turned into acetate then released into the blood

Question 23

difference between alcohol DH and MEOS CYP2E1

Answer 23

ADH has a low Km for ethanol so ethanol is its main substrate but MEOS CYP2E1 has a higher Km so it is induced when excess ethanol

Question 24

which has a higher Km – mitochondrial ALDH-2 or cytosolic ALDH-1

Answer 24

cytosolic ALDH-1 has a higher Km which is why acetaldehyde is used as its substrate only if high amounts of ethanol —> higher amounts of acetaldehyde

Question 25

what happens if drug is given that inhibits ALDH

Answer 25

build up of acetaldehyde in the cytosol ---> flushing and elevated heart rate after small amounts of ethanol

Question 26

where do you form NADH in ethanol breakdown

Answer 26

steps that use enzyme ADH and ALDH

Question 27

ratio of NADH/NAD+ when high ethanol

Answer 27

high NADH/NAD+

Question 28

what happens as a result of high NADH/NAD+ due to high ethanol levels

Answer 28

gluconeogenesis impaired, lactate build up so pyruvate lost, oxaloacetate can't be formed from malate, glycerol 3-P cant form DHAP

Question 29

conditions that arise from high NADH/NAD+ level

Answer 29

hypoglycemia, lactic acidemia, gout, hyperlipidemia, ketoacidosis, acetate (in blood), inhibition of drug metabolism

Question 30

what happens to acetate released by liver into blood

Answer 30

acetate it taken up by muscle and forms acetyl CoA using acetyl synthetase --->TCA cycle

Question 31

what happens to the acetylaldehyde released by liver in ethanol abuse

Answer 31

``` inhibits VLDL release--> fatty liver binds to SH inhibits release of proteins including clotting factors toxic to brain alcohol induced hepatitis ```

Question 32

drug used as treatment for alcoholism

Answer 32

disulfiram

Question 33

how does disulfiram treat alcoholism and what happens if large intake of alcohol with drug

Answer 33

prevents alcohol consumption because of flushing and nausea that comes with amount of alcohol if large intake of alcohol with drug, amount of acetyaldehyde increases 5-10 times

Question 34

how do you treat methanol or ethylene glycol poisoning

Answer 34

inhibit alcohol dehydrogenase by ethanol or a competitive drug (Fomepizole), bicarbonate to reverse severe acidosis, and hemodialysis

Question 35

what does inhibiting alcohol dehydrogenase do in methanol poisoning

Answer 35

it stops methanol from reacting with alcohol dehydrogenase to form formaldehyde which can lead to blindness or mental problems

Question 36

how does using ethanol treat methanol poisoning

Answer 36

ethanol has a higher affinity for alcohol dehydrogenase than methanol so it will react with it rather than methanol

Question 37

what happens when ethylene glycol is ingested

Answer 37

it reacts with alcohol dehydrogenase to form glcoaldehyde ---> kidney failure and death because of formation of calcium oxalate