Alcohol and Xenobiotic Metabolism of the Liver Flashcards
phases of drug metabolism in the liver
phase I: hydroxylation by microsomal CYP450
phase II: conjugation using UDP glucuronic acid, PAPs (sulfate), Glutathione, AA
where do the phases of drug metabolism occur
phase I is in the ER and phase II in they cytosol
reason why we detoxify alcohol/xenobiotics
to increase their water solubility (for excretion) in the two phases
do all drugs go through both phases
No some skip phase I hence not using CYP450
what does CYP450 do to drugs
can inactivate it, make it more polar to be excreted, activate it, convert it to a toxic metabolite
what does CYP3A4 rep/do
1/3 of CYP450 and acts on more than half of the therapeutic drugs like statin and tamoxifen
what does CYP2E1 do
ethanol metabolism
what does CYP450 contain
heme containing enzyme —-induced by drugs and ethanol
provides CYP450 the NADPH it needs to catalyze its reaction
CYP450 reductase
what induces CYP450
increase transcription of mRNA of CYP450, drugs like phenobarbitol, ethanol consumption (specifically activates the CYP2E1 –part of microsomal ethanol oxidizing system MEOS)
what patients do you avoid giving phenobarbitol to
those with acute intermittent porphyria —if you stimulate heme synthesis in them leads to higher ALA (similar to GABA hence cell death)
grapefruit juice can inactive which cytochrome
CYP3A4
what happens then when CYP3A4 has been inactivated
drugs like statin and tamoxifen would be less inactive
why must one increase the amount of warfarin intake if drug is taken together with phenobarbital
phenobarbital degrades warfarin so more must be taken to overcome
what happens if taken high warfarin with phenobaribital then one stops taken phenobarbital but continues high dose of warfarin
warfarin level too high hence dangerous bleeding can occur
what happens with acetaminophen (tylenol) in the body of chronic alcoholics
it is more processed by CYP2E1 and leads to toxic compound NAPQI
fate of NAPQI
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
how do you treat acetaminophen poisoning
with drug acetadote – has N acetyl cysteine that binds directly to NAPQI and provides cysteine for glutathione synthesis
main cells to metabolizes most of blood ethanol to acetaldehyde
hepatocytes
enzymes that form acetaldehyde from ethanol
alcohol DH (low Km) and MEOS CYP2E1 (high Km)
why do asians tend get drunk a lot quicker than most
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
fate of acetaldehyde in blood
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
difference between alcohol DH and MEOS CYP2E1
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
which has a higher Km – mitochondrial ALDH-2 or cytosolic ALDH-1
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
what happens if drug is given that inhibits ALDH
build up of acetaldehyde in the cytosol —> flushing and elevated heart rate after small amounts of ethanol
where do you form NADH in ethanol breakdown
steps that use enzyme ADH and ALDH
ratio of NADH/NAD+ when high ethanol
high NADH/NAD+
what happens as a result of high NADH/NAD+ due to high ethanol levels
gluconeogenesis impaired, lactate build up so pyruvate lost, oxaloacetate can’t be formed from malate, glycerol 3-P cant form DHAP
conditions that arise from high NADH/NAD+ level
hypoglycemia, lactic acidemia, gout, hyperlipidemia, ketoacidosis, acetate (in blood), inhibition of drug metabolism
what happens to acetate released by liver into blood
acetate it taken up by muscle and forms acetyl CoA using acetyl synthetase —>TCA cycle
what happens to the acetylaldehyde released by liver in ethanol abuse
inhibits VLDL release--> fatty liver binds to SH inhibits release of proteins including clotting factors toxic to brain alcohol induced hepatitis
drug used as treatment for alcoholism
disulfiram
how does disulfiram treat alcoholism and what happens if large intake of alcohol with drug
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
how do you treat methanol or ethylene glycol poisoning
inhibit alcohol dehydrogenase by ethanol or a competitive drug (Fomepizole), bicarbonate to reverse severe acidosis, and hemodialysis
what does inhibiting alcohol dehydrogenase do in methanol poisoning
it stops methanol from reacting with alcohol dehydrogenase to form formaldehyde which can lead to blindness or mental problems
how does using ethanol treat methanol poisoning
ethanol has a higher affinity for alcohol dehydrogenase than methanol so it will react with it rather than methanol
what happens when ethylene glycol is ingested
it reacts with alcohol dehydrogenase to form glcoaldehyde —> kidney failure and death because of formation of calcium oxalate
