Biochemistry-Hepatotoxic Drugs Flashcards
How many calories per gram do the different macronutrients provide?
Protein: 4 Cal/g, Carbs: 4 Cal/g, Alcohol: 7 Cal/g, Fat: 9 Cal/g
How many calories does an alcoholic typically get from drinking alcohol?
50.00%
What is the major pathway of alcohol metabolism?
Ethanol is taken to acetaldehyde by alcohol dehydrogenase. Acetaldehyde goes to acetate by aldehyde dehydrogenase. Acetate goes to other tissues and acetyl CoA synthetase makes acetyl CoA that then can enter the TCA cycle.
How does alcohol cause depletion of NAD+?
NAD+ is used in both reactions by alcohol dehydrogenase and aldehyde dehydrogenase.
What is the minor pathway of alcohol metabolism?
Microsomal Ethanol Oxidation System (MEOS) in the smooth ER, which proliferates in heavy drinkers.
How is the NADPH regenerated for continued alcohol metabolism?
Pentose phosphate pathway.
What enzyme is key in metabolism of alcohol in the MEOS?
CYP450 and Cytochrome P450 reductase. NADPH donates electrons to CYP450 reductase. Reductase transfers those electrons to the heme group of CYP450. CYP450 transfers those electrons to O2 to create a ROS. Oxygen inserts into ethanol, creating acetaldehyde.
What are 2 reasons MEOS is thought to be hepatotoxic?
As ROS spin around P450, they sometimes pop off of F3+ and cause cell damage. Another reason is that acetaldehyde is produced, and may be in excess to what the liver can handle and result in damage.
How does muscle take acetate sent from the liver to acetyl CoA?
Acetyl CoA Synthetase. Remember that this takes 2 high energy bonds to run this reaction.
How much ATP do you get from one molecule of ethanol in the major ethanol metabolic pathway?
- EtOH -> Acetaldehyde = +2.5 ATP (1 NADH). Acetaldehyde -> Acetate = +2.5 ATP (1 NADH). Acetate -> Acetyl CoA = -2 ATP. Acetyl CoA = +10 ATP.
How much ATP do you get from metabolism of ethanol in the liver? What about total ATP yield?
The major pathway and MEOS balance out to yield no net ATP production in the liver. However, MEOS still produces acetaldehyde which goes to acetate and Acetyle CoA which yield 8 ATP in peripheral tissue. 8/13 * 7 = 4.3 Cal/g total.
What foods should you decrease in your diet if you want to calorie balance your alcohol intake?
Fats, to prevent development of fatty liver.
How is it possible that someone can drink 1800 Cal of ethanol and not gain any weight?
Activation of MEOS yields no net ATP and alcohol uncouples oxidative phosphorylation so no ATP is produced.
A man walks into a bar and orders two drinks. He hasn’t eaten in two days. He passes out and labs reveal hypoglycemia. What caused his condition?
Despite getting calories from alcohol, ethanol cannot go to glucose via gluconeogenesis because it first goes to acetyl CoA. The conversion of pyruvate to acetyl CoA by pyruvated DH is irreversible and thus you can’t get back to glucose. Also note that you can’t do it via OAA because you lose 2C of acetyl CoA in the TCA cycle.
With ethanol conversion to acetaldehyde and acetate, you increase the cytoplasmic ratio of NADH/NAD+. What effect does this have on the cell?
1) Acetaldehyde is a toxin 2) Beta-oxidation doesn’t happen due to lack of NAD+ and fatty acids build up and are esterified to fat in the liver 3) TCA cycle shuts down b/c lots of energy is already coming from ethanol, acetyl CoA levels rise, ketone bodies build up and you get ketoacidosis 4) Pyruvate is reduced to lactate b/c NADH levels are high and prevents gluconeogenesis = hypoglycemia and lactate acidemia -> gout 5) OAA is reduced to malate b/c NADH levels are high and prevents gluocneogenesis -> hypoglycemia
Why shouldn’t you take acetaminophen when you are hung over?
Normally when you take acetaminophen, APAP is metabolized by glucuronyl transferase or sulfotransferase and very little is made into NAPQI and secreted as mercapturic acid. When you drink, you induce the enzyme CYP2E1 that takes APAP to NAPQI, which isn’t a problem when BAC is high because the enzyme is saturated. It is a problem when you take tylenol a few days later because CYP2E1 levels are still high and you get a lot of hepatotoxic NAPQI build up. NAPQI saturates glutathione and you get more liver damage by ROS.
