MMT: metabolism of ethanol II Flashcards
What is the root cause of many of the acute effects of ethanol?
The buildup of NADH from the ADH/ALDH metabolic pathway.
What is the issue with NADH buildup?
It reduces B-oxidation, leading to a buildup of fatty acids.
How can hyperlipidemia develop as an acute effect of alcohol?
Glucose and NADH will form G3P, which combines with excess fatty acids due to NADH accumulation to form TGs. This causes hyperlipidemia.
How can ketoacidosis occur as an acute effect of ethanol?
High NADH suppresses the TCA cycle. This causes acetyl CoA to buildup and ketone body production to increase, leading to ketoacidosis from BHB and acetoacetate.
How can lactate acidemia form as an acute effect of ethanol?
The excess NADH encourages pyruvate formed from glucose to convert to lactate.
How can gout occur as an acute effect of ethanol?
Excess lactic acid produced due to TCA cycle being shut down and pyruvate converting to lactate competed with uric acid for excretion. This may lead to uric acid buildup and resulting gout.
How does hypoglycemia form as an acute effect of alcohol?
Gluconeogenic precursors that get converted to pyruvate are blocked for the pathway due to the excess NADH impacting the system. This results in low glucose and further production of lactate by pyruvate.
What is the main molecule responsible for irreversible effects of ethanol?
Acetaldehyde.
What are the 2 forms of irreversible liver damage?
Hepatitis, cirrhosis.
What is a form of reversible liver damage?
Fatty liver.
What factors lead to alcohol induced hepatitis?
Lipid/protein accumulation, hepatocyte swelling, oxidative damage, low ETC activity.
Describe how impaired protein secretion can occur as a chronic complication of ethanol.
Acetaldehyde binds to amino acids, including those in the cytoskeletal. The cytoskeletal damage and damage to proteins leads to a prevention of protein secretion.
How does chronic ethanol use relate to glutathione?
Excess acetaldehyde will tie up the glutathione, preventing the hepatocytes from properly breaking down toxic radicals. This may lead to lipid peroxidation.
Describe how lipid peroxidation can occur as a chronic complication of ethanol.
CYP2E1 from the MEOS pathway results in lower NADPH, since it consumes it, preventing regeneration of reduced glutathione that normally is involved in breaking down toxic radicals. These radicals may lead to lipid peroxidation.
How does acetaldehyde impact the mitochondria?
It damages proteins of the ETC and leads to accumulation of NADH/NADPH that reduces the ALDH function that forms acetate from acetaldehyde. This leads to an even larger buildup of acetaldehyde.
Describe how lipid accumulation can occur as a chronic complication of ethanol.
Fatty acids in excess due to B-oxidation suppression leads to excess TG formation/hyperlipidemia. When this process happens chronically and VLDL secretion is impacted due to the damaging of proteins by acetaldehyde, we get an accumulation of these lipids in the liver called alcohol fatty steatosis.
What is alcoholic fatty steatosis?
Alcohol fatty steatosis is the accumulation of lipids in the liver due to chronic alcohol use.
What is a major adverse effect of the increased protein concentration in hepatocytes resulting from chronic alcohol use?
The osmotic pressure increases, drawing in more water. This leads to hepatocytes swelling and bursting, releasing ALT and AST.
What is an indicator of hepatocyte damage in the blood?
Increased ALT and AST levels.
Describe portal hypertension in chronic alcohol use.
Acetaldehyde in the liver can form adducts with proteins. These can’t always be secreted, causing increased osmotic pressure and increased water being drawn into hepatocytes. This results in portal hypertension and esophageal varices.
Describe esophageal varices in chronic alcohol use.
Portal hypertension can cause superficial veins in the lower esophagus to swell. If these burst, people can bleed to death.
What is a major player in ROS formation as a result of ethanol?
CYP2E1! The heme iron in the enzyme is in a high-spin state that favors ROS formation.
What is the main target of free radicals?
Membrane lipids.
Describe cardiomyopathy in alcohol users.
Acetaldehyde build-up in the liver and transferring to peripheral tissues such as the heart damaged proteins, weakening the heart and causing it to fail.
What do ADH and ALDH convert methanol to?
Formaldehyde and formic acid respectively.
Is methanol toxic?
Incredibly; formaldehyde is neurotoxic as well.
What do ADH and ALDH convert ethylene glycol to?
Oxalic acid.
Why are methanol and ethylene glycol so toxic?
They form all of these intermediate aldehydes that are toxic. The aldehydes can cross link and create issues as well. The oxalic acid resulting from them can also cause metabolic acidosis and kidney failure.
How can we treat methanol/ethylene glycol poisoning?
Giving ethanol or fomepizole. Ethanol competes for the enzymes and prevents metabolizing of methanol and ethylene glycol, and fomepizole inhibits ADH and the MEOS system.
What can oxalate do to the kidneys?
Cause crystals/stones or renal failure.