MMT: metabolism of ethanol I Flashcards
Where is ethanol mostly metabolized?
The liver
What are the two alcohol metabolizing systems?
Liver alcohol dehydrogenase or liver microsomal ethanol oxidizing system (higher levels of consumption)
What is the major metabolite of ethanol?
Acetaldehyde
Describe catalase in terms of ethanol metabolism.
Catalase is present in peroxisomes and is capable of oxidizing ethanol using hydrogen peroxide. This really only happens with high levels of ethanol.
What are the main metabolic methods of ethanol in peripheral tissues such as the brain and heart?
CYP2E1 (microsomal ethanol oxidizing system) and catalase
Describe the overall process of ethanol metabolism in the liver.
- Ethanol enters the liver via the portal system. 2. ADH in the cytoplasm of hepatocytes converts ethanol to acetaldehyde. 3. Acetaldehyde enters mitochondria, where ALDH converts it to acetate. 4. Acetate exits hepatocytes and moves to peripheral tissues, where it can convert to acetyl CoA and take part in the TCA cycle.
What is produced by ADH and ALDH other than their main metabolites?
NADH
Where is most of acetaldehyde converted to acetate?
In the mitochondria via ALDH2. Some happens in the cytoplasm via ALDH1.
What are ADH2 and ADH1B2?
Isoforms of ADH that have increased activity and may produce acetaldehyde too fast, preventing it from properly converting to acetate and potentially causing problems.
What are class IV isozymes of ADH?
Isozymes in the upper GI tract that produce toxic acetaldehyde when alcohol concentrations are high, making them associated with GI cancers seen in heavy drinking.
What is ALDH2*2?
A variant of ALDH with a super high Km, meaning it isn’t great at recognizing acetaldehyde. People with this can’t tolerate alcohol well because acetaldehyde can accumulate to toxic levels. Their skin flushes red.
What is disulfiram?
An inhibitor of ALDH that is given for avoidance therapy. It will cause nausea and vomiting and hopefully creates an aversion, but often doesn’t work.
Describe microsomal ethanol oxidation system (MEOS).
MEOS oxidizes ethanol to acetaldehyde via CYP2E1. It has a higher Km for ethanol, making it mainly active at higher levels of drinking.
What kind of enzyme is CYP2E1?
P450
What is produced by CYP2E1 besides its major metabolite?
NADP+
What is the main issue with CYP2E1?
It produces acetaldehyde too fast, to a point where ALDH cannot keep up. This leads to an accumulation that may damage the liver, heart, brain, and other peripheral tissues. They also produce free radicals that may cause hepatic damage and cirrhosis.
What happens when someone who drinks a lot takes acetaminophen?
The CYP2E1 and acetaminophen result in production of NAPQI, a toxic metabolite. In smaller amounts it can be cleared by glutathione conjugation.
Why is acetaminophen harmful to alcoholics?
Upregulated CYP2E1 activity and acetaminophen results in high NAPQI production that leads to depletion of glutathione and leaves space for NAPQI to wreak havoc and damage the liver.
What functional zone of the liver is the first to undergo necrosis in acetaminophen overdose?
Pericentral zone (zone 3)
Describe the interaction of ethanol and phenobarbital.
Phenobarbital increases CYP2B1 and CYP2B2 that metabolize it, while ethanol inhibits these enzymes. This causes phenobarbital to reach toxic levels. Chronic users are at higher risk.
How much energy do we produce in the main ethanol consumption pathway?
10 P bonds
How much energy do we produce in the MEOS pathway?
8 P bonds, due to the consumption of NADPH.
Why are spirits considered an empty calorie?
It contains metabolic energy but little to no vitamins or essential nutrients.
Are beer and wine empty calories?
No! They may contain antioxidants or other small amounts of vitamins.
What is the most common vitamin deficiency in alcoholics?
B1 (thiamine)
Why can alcoholics develop malnutrition?
Poor appetite, damage of microvilli, damage to the liver leading to issues with storing nutrients.
What is Wernicke-Korsakoff syndrome?
An alcohol-related thiamine deficiency.
Why is the brain sensitive to thiamine deficiency?
It needs a lot of energy! Thiamine is a huge cofactor for enzymes needed to produce energy, so a lack of it is an issue for the brain as it will have to rely exclusively on glycolysis for energy.
What enzymes is thiamine pyrophosphate a cofactor for?
Pyruvate dehydrogenase complex, a-ketoglutarate dehydrogenase complex, branched chain a-ketoacid dehydrogenase, transketolase.
How do we test for thiamine deficiency?
Transketolase
Why do we have to give thiamine with glucose in hypoglycemic alcoholics?
If we do not give thiamine, the glucose converts to pyruvate but then cannot participate in the TCA cycle. As a result, it will form lactate. This harms the brain and may lead to encephalopathy and death. Giving thiamine allows the enzymes requiring it as a cofactor to be functional, allowing the glucose to be used in TCA cycles for energy.
