21: Alcohol Metabolism Flashcards
Ethanol metabolism occurs primarily in the _____ and is a two step _____ sequence leading to the production of _____ and ______.
Ethanol metabolism occurs primarily in the liver and is a two step oxidation sequence leading to the production of acetate and NADH.
Acetate is converted to _____ which is utilized for energy production in most of the body tissues.
Acetate is converted to acetyl CoA which is utilized for energy production in most of the body tissues.
When ethanol in the blood levels are high then the ____________ is induced.
When ethanol in the blood levels are high then the microsomal ethanol oxidizing system (MEOS) CYP2E1 is induced.
Acute effects of ethanol ingestion, due to elevated NADH/NAD+ ratio, include:
- Inhibition of fatty acid oxidation.
- Ketogenesis
- Hyperlipidemia
- Inhibition of gluconeogenesis
- Lactic acidosis
- Hyperuricemia
Chronic effects of ethanol ingestion include:
- Hepatic steatosis
- Hepatitis
- Fibrosis
- Cirrhosis
The chronic effects of ethanol ingestion are due to ______ and ______ produced as products of ethanol metabolism.
The chronic effects of ethanol ingestion are due to acetaldehyde and ROS produced as products of ethanol metabolism.
Ethanol that we consume is converted to ______ primarily in the liver with the generation of ______.
This is a two step process: first the ______ of ethanol to acetaldehyde, which is toxic, and then the ______ of acetaldehyde to acetate.
The first step, ethanol to acetaldehyde, is catalyzed by ________ in the cytosol and the second (acetaldehyde to acetate) by _____ in the mitochondria.
Most of the acetate enters the blood and travels to muscle and other tissues where it is converted to acetyl CoA by ________ and is oxidized by the Krebs cycle.
10-20% of ingested alcohol is oxidized through a liver _______ comprised of ______ enzymes (primarily CYP2E1) in the ER.
Ethanol is mainly absorbed from the _______ by passive diffusion.
Ethanol then enters the blood where most of it is metabolized in the _____ and 2‐10% is excreted through the _____ or _____. This is a second route for EtOH metabolism in the liver. The cyt P45o mixed function oxidase isozyme involved is ______ which converts ethanol to acetaldehyde using ______ as an additional electron donor and ______ as an electron acceptor.
The primary route of ethanol metabolism in the liver is through ADH, in the cytosol, converting ______ to ________ with production of NADH.
The ________ which is not further metabolized can damage the liver and can also enter the blood exerting toxic effects on other tissues.
Most of the acetaldehyde formed is further metabolized by a low Km _______ which converts acetaldehyde to acetate with production of NADH.
Acetate is nontoxic & is converted to acetyl CoA, which can enter the ______ or ________. The acetate in the blood is converted to acetyl CoA in the muscle & tissues.
Ethanol that we consume is converted to acetate primarily in the liver with the generation of NADH.
This is a two step process: first the oxidation of ethanol to acetaldehyde, which is toxic, and then the oxidation of acetaldehyde to acetate.
The first step, ethanol to acetaldehyde, is catalyzed by alcohol dehydrogenase (ADH) in the cytosol and the second (acetaldehyde to acetate) by acetaldehyde dehydrogenase (ALDH) in the mitochondria.
Most of the acetate enters the blood and travels to muscle and other tissues where it is converted to acetyl CoA by acetyl CoA synthetase and is oxidized by the Krebs cycle.
10-20% of ingested alcohol is oxidized through a liver microsomal alcohol oxidizing system (MEOS) comprised of cyt P450 enzymes (primarily CYP2E1) in the ER.
Ethanol is mainly absorbed from the intestine by passive diffusion.
Ethanol then enters the blood where most of it is metabolized in the liver and 2‐10% is excreted through the lungs or kidneys. This is a second route for EtOH metabolism in the liver. The cyt P45o mixed function oxidase isozyme involved is CYP2E1 which converts ethanol to acetaldehyde using NADPH as an additional electron donor and O2 as an electron acceptor.
The primary route of ethanol metabolism in the liver is through ADH, in the cytosol, converting Ethanol to Acetaldehyde with production of NADH.
The acetaldehyde which is not further metabolized can damage the liver and can also enter the blood exerting toxic effects on other tissues.
Most of the acetaldehyde formed is further metabolized by a low Km ALDH which converts acetaldehyde to acetate with production of NADH.
Acetate is nontoxic & is converted to acetyl CoA, which can enter the Krebs cycle or fatty acid synthesis. The acetate in the blood is converted to acetyl CoA in the muscle & tissues.
There are a family of ADH Isozymes that differ in their specificity of chain length of the alcohol substrate & @ high concentrations, ethanol can be metabolized by many members of the ADH family.
ADH1 =
ADH 4 =
ADH 2 =
ADH 3 =
There are a family of ADH Isozymes that differ in their specificity of chain length of the alcohol substrate & @ high concentrations, ethanol can be metabolized by many members of the ADH family.
ADH1 = highest affinity (lowest Km) & in liver
ADH 2 = liver & lower GI tract
ADH 3 = inactive to ethanol but active toward long chain alcohols
ADH 4 = upper GI
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction.
_________ catalyzes the oxidation of acetaldehyde to acetate with generation of NADH.
> 80% of acetaldehyde oxidation in our liver is catalyzed by the mitochondrial isozyme ______. ALDH2 has high affinity for acetaldehyde (lowest Km). The rest is carried out by a cytoplasmic isozyme _______.
Accumulation of _______ due to inactive ALDH2 causes flushing, nausea and vomiting and a distaste for alcoholic beverages.
Alcoholics are frequently treated with ALDH _______ (ex. disulfiram) which help them abstain (buildup of Acetaldehyde).
The metabolism of the acetate to acetyl CoA requires _________.
In liver the primary isoform is _____ which is a cytosolic enzyme which generates acetyl CoA for the pathways of cholesterol and fatty acid synthesis.
Acetaldehyde dehydrogenases catalyzes the oxidation of acetaldehyde to acetate with generation of NADH.
> 80% of acetaldehyde oxidation in our liver is catalyzed by the mitochondrial isozyme ALDH2. ALDH2 has high affinity for acetaldehyde (lowest Km). The rest is carried out by a cytoplasmic isozyme ALDH1.
Accumulation of acetaldehyde due to inactive ALDH2 causes flushing, nausea and vomiting and a distaste for alcoholic beverages. (A single amino acid substitution leads to an allelic variant designated ALDH2*2 which has 23 fold higher Km and 35 fold lower Vmax. Homozygosity for this allele provides absolute protection against alcoholism)
Alcoholics are frequently treated with ALDH Inhibitors (ex. disulfiram) which help them abstain (buildup of Acetaldehyde).
The metabolism of the acetate to acetyl CoA requires acetyl CoA synthetase (ACS).
In liver the primary isoform is ACS I which is a cytosolic enzyme which generates acetyl CoA for the pathways of cholesterol and fatty acid synthesis.
Discuss the importance of the cytochrome P450 superfamily & what CYP2E1 does.
Ethanol is also oxidized in the liver by MEOS comprised of ER cytochrome P450 enzymes.
Ethanol and NADPH both donate electrons in the reaction which reduces O2 to 2H2O.
Cytochome P450 superfamuly has 2 catalytic components: 1) Cytochome P450 reductase which transfers e- from NADPH 2) Cytochrome P450 which contains binding sites for O2 & EtoH & carries out the rxn.
CYP2E1 is one of over 100 cytochrome P450 mixed function oxidases . CYP2E1 is the cytochrome P450 with the highest activity when ethanol is substrate, but other P450s are also involved. MEOS refers to the combined ethanol oxidizing activity of all P4502. CYP2E1 has a much higher Km for ethanol than ADH1 and therefore becomes more involved in ethanol oxidation when large quantities of ethanol are consumed.
The products of alcohol oxidation, by CYP2E1, include acetaldehyde and ROS resulting in oxidative stress and cellular damage. CYP2E1 induction increases ethanol clearance from the blood but produces acetaldehyde faster than it can be metabolized by ALDH resulting in damage to the liver and other tissues.
Describe variations in ethanol metabolism among people:
Variations in ethanol metabolism among people:
- Genetic differences in ADH & CYP2E1
- ADH decreases & CYP2E1 with increased EtOH consumption.
- Women have higher levels of blood ethanol than men due to less gastric ADH activity, smaller size, & less water space.
- The higher the quantity of ethanol consumed, the higher the involvement of CYP2E1 & the higher the levels of acetaldehyde & ROS.
Describe the acute & chronic effects of ethanol on the liver & on metabolism.
Acute effects on liver metabolism include inhibition of fatty acid oxidation and stimulation of TAG synthesis leading to a fatty liver; and ketoacidosis or lactic acidosis causing hypo or hyperglycemia depending on the dietary state. These effects are considered reversible.
Acetaldehyde and ROS generated from ethanol metabolism can result in alcohol induced hepatitis characterized by liver inflammation and necrotic cell death; or damage to hepatocytes leading to cirrhosis characterized by fibrosis (scarring), altered blood flow, and loss of liver function.
Acute effects of ethanol consumption on lipid metabolism are the result of increased NADH/NAD+ ratio.
Ethanol oxidation by ADH and ALDH increases NADH/NAD+.
High NADH/NAD+ ratio inhibits fatty acid oxidation and the TCA cycle leading to accumulation free fatty acids. VLDL accumulates in the liver leading to fatty liver = ethanol induced lipidemia.
Inhibition of the TCA cycle causes acetyl CoA to enter the ketone body pathway raising their levels (ketoacidosis).
Very high NADH/NAD+ is that there is increased production of
lactate by lactate dehydrogenase. This results in lactic acidosis. Increase of blood lactate decreases uric acid excretion by the
kidney. Patients with gout therefore are advised not to drink
excessively.
Drinking alcohol in the fasting state blocks gluconeogenisis & can cause hypoglycemia. However, drinking alcohol with a meal causes transient hyperglycemia because the high NADH/NAD+ inhibits glycolysis at the glyceraldehyde 3‐P dehydrogenase step.
Chronic alcohol consumption leads to increased acetaldehyde and ROS in the liver and released into the blood. This causes a decrease in protein synthesis because the acetaldehyde adducts with amino acids.
This accumulation of proteins causes water to enter into hepatocytes with resulting swelling of the liver resulting in portal hypertension and disruption of hepatic architecture. Cell damage leads to release of hepatic enzymes such as alanine aminotransferase (ALT) and aspartate amino transferase (AST).
There is increased oxidative damage due to ROS & MEOS increase. Peroxidation of lipids in the mitochondrial inner membrane and oxidative damage to proteins inhibits electron transport and diminishes acetaldehyde conversion to acetate.
Describe fibrosis & cirrhosis.
Chronic insult to the liver via alcohol use causes fibrosis which is an overproduction of extracellular matrix which progresses to sclerosis which involves degeneration of the components of the extracellular matrix. 20% of heavy drinkers progress from fibrosis to Cirrhosis.
Cirrhosis = irreversible damaged. Initially liver is enlarged, full of fat and crossed with collagen fibers (fibrosis) and have nodules of ballooning hepatocytes between the fibers. As liver function is lost the liver becomes shrunken= Cirrhosis. Loss of metabolic functions include protein synthesis and secretion, detoxification pathways, the ability to incorporate amino groups into urea leading to toxic levels of ammonia, and diminished conjugation and secretion of bilirubin occurs with increased accumulation of bilirubin in the blood. The increased blood bilirubin is deposited in many tissues including skin and the sclera of the eyes. This causes the yellow color of the patient = jaundice.
State whether the following diseases have enviornmental components, genetic components, or both. Obesity, alcoholism, jaundice, liver fibrosis.
State whether the following diseases have enviornmental components, genetic components, or both. Obesity = both (excessive nutrients), alcoholism = both (alcohol addiction), jaundice = enviornmental (reduced ability to conjugate & solubilze billirubin), liver fibrosis = enviornmental (due to acetaldehyde accumulation from alcoholism).
