Question 1

Induction of CYP2E1 would be expected to result in which of the following?&#10;A) decreased rate of ethanol clearance from the blood&#10;B) decreased rate of acetaldehyde production&#10;C) increased level of alcohol tolerance&#10;D) protection from alcohol-induced hepatic necrosis&#10;E) reduced likelihood of free radical production

Accepted Answer

Induction of CYP2E1 increases the metabolism of ethanol, leading to faster clearance and increased production of acetaldehyde, which can contribute to alcohol tolerance. However, it may also increase the risk of liver damage and free radical production. The primary pathway of ethanol metabolism is that initiated by ADH. The second major pathway for ethanol metabolism is the microsomal ethanol-oxidizing system (MEOS), which involves the cytochrome P450 enzyme CYP2E1. The MEOS pathway is induced in individuals who chronically consume alcohol, resulting in higher rates of metabolism leading to increased tolerance to alcohol ingestion

Question 2

Which of the following chronic effects of alcohol consumption is irreversible?&#10;A) activation of triglyceride synthesis&#10;B) inhibition of fatty acid oxidation&#10;C) ketoacidosis&#10;D) lactic acidosis&#10;E) liver cirrhosis

Accepted Answer

Liver cirrhosis is an irreversible condition characterized by permanent scarring and damage to the liver tissue due to chronic alcohol consumption.  Chronic ethanol consumption and alcohol metabolism contributes to the spectrum of metabolic disorders frequently found in alcoholics. These disorders include fatty liver syndromes such as NAFLD and NASH, hyperlipidemia, lactic acidosis, ketoacidosis, and hyperuricemia. The first stage of liver damage following chronic alcohol consumption is the appearance of fatty liver, which is followed by inflammation, apoptosis, fibrosis, and finally cirrhosis. These negative and toxic changes within the liver are irreversible even when alcohol consumption is terminated.

Question 3

Acetate, derived from the oxidation of ethanol, has which of the following fate?&#10;A) due to its toxicity it leads to necrosis of the liver&#10;B) it directly enters the TCA cycle and is oxidized&#10;C) it is converted into NADH via the action of ADH&#10;D) it is excreted in the bile&#10;E) it is taken up by nonhepatic tissues and converted to acetyl-CoA

Accepted Answer

Acetate is converted to acetyl-CoA in nonhepatic tissues, which can then enter the TCA cycle for energy production. Acetate, from whatever source, is converted to acetyl-CoA by ATP-dependent acetylCoA synthetases (AceCS). Following the consumption of ethanol, acetate levels can be elevated by as much as 20-fold. The primary causes of fatty liver syndrome (hepatic steatosis), induced by excess alcohol consumption, are the altered NADH/NAD₊ levels that in turn inhibits gluconeogenesis, inhibits fatty acid oxidation, and inhibits the activity of the TCA cycle. Each of these inhibited pathways results in the diversion of acetyl-CoA into de novo fatty acid synthesis.

Question 4

Which of the following events would be most likely to be observed following acute consumption of alcohol?&#10;A) activation of fatty acid oxidation&#10;B) increased rate of gluconeogenesis&#10;C) increased ratio of NAD+ to NADH&#10;D) inhibition of ketogenesis&#10;E) lactic acidosis

Accepted Answer

Acute alcohol consumption leads to an increased NADH/NAD+ ratio, which inhibits gluconeogenesis and fatty acid oxidation, and promotes lactic acid production, leading to lactic acidosis.  The majority of the aberrant metabolic effects of ethanol intoxication stem from the actions of ADH and ALDH and the resultant cellular imbalance in the NADH:NAD+ ratio. Additionally, there is an increased rate of hepatic lactate production due to the effect of increased NADH on direction of the hepatic lactate dehydrogenase (LDH) reaction. This reversal of the LDH reaction in hepatocytes results in reduced capacity of the liver to divert lactate into glucose via gluconeogenesis. resulting in elevated lactate levels in the blood, leading to lactic acidosis.

Question 5

Alcoholism is sometimes treated with the drug disulfiram. This drug deters the consumption of alcohol by which of the following mechanisms?&#10;A) activating the excessive metabolism of ethanol to acetate resulting in rapid inebriation with limited alcohol consumption&#10;B) blocking the conversion of acetaldehyde to acetate resulting in rapid accumulation of toxic acetaldehyde adducts&#10;C) inhibiting ethanol absorption so that an individual cannot become intoxicated&#10;D) inhibiting the conversion of ethanol to acetaldehyde, thereby, causing ethanol to be excreted before it can be metabolized&#10;E) preventing the excretion of acetate resulting in severe nausea and vomiting

Accepted Answer

Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, leading to the accumulation of acetaldehyde when alcohol is consumed, which causes unpleasant effects.  Disulfiram blocks the processing of alcohol in the body by inhibiting acetaldehyde dehydrogenase, thus causing an unpleasant reaction when alcohol is consumed due to a rapid increase in the production of toxic acetaldehyde adducts.

Question 6

Ethanol metabolism is associated with a disruption in the NADH:NAD+ ratio. Which of the following is one major consequence of this
Disruption?

A) altered membrane fluidity resulting in decreased hepatocyte function
B) hyperglycemia due to increased rates of hepatic gluconeogenesis
C) increased production of glycerol 3-phosphate contributing to triglyceride production
D) increased TCA cycle activity resulting in increased oxygen consumption
E) potentiation of CNS activity

Accepted Answer

The increased NADH:NAD+ ratio from ethanol metabolism leads to an increase in glycerol 3-phosphate, which contributes to triglyceride production and can result in fatty liver.  The altered NADH:NAD+ ratio that in turn inhibits gluconeogenesis, inhibits fatty acid oxidation and the activity of the TCA cycle. The reduction in NAD+ impairs the flux of glucose through glycolysis at the glyceraldehyde-3-phosphate dehydrogenase reaction, thereby limiting energy production. The reduction in cytosolic NAD+ leads to reduced activity of glycerol- 3-phosphate dehydrogenase (in the glycerol 3-phosphate to DHAP direction), resulting in increased levels of glycerol 3-phosphate which is the backbone for the synthesis of the triglycerides. Both of these 2 events lead to fatty acid deposition in the liver leading to fatty liver syndrome and excessive levels of lipids in the blood, referred to as hyperlipidemia.

Question 7

Which of the following is the primary mode of metabolism of ethanol?&#10;A) excretion through the kidneys&#10;B) exhalation from the lungs&#10;C) oxidation in the kidneys&#10;D) oxidation in the liver&#10;E) oxidation in the lungs

Accepted Answer

Ethanol is primarily metabolized in the liver through oxidation, where it is converted to acetaldehyde by the enzyme alcohol dehydrogenase.  Metabolism of ethanol occurs within the liver and involves oxidation to acetaldehyde and then to acetate catalyzed by ADH and ALDH, respectively

Question 8

You are examining a patient who complains of severe headaches and flushing of the face, neck, and upper chest following the consumption of a glass of white wine. After taking a history, you find that other members of his family also suffer from similar symptoms following alcohol consumption. Given this patient's symptoms and history, which of the following is most likely his associated genotype?

A) ADH1A and ALDH2*2
B) ADH1B*1 and ALDH2*2
C) ADH1C*1 and ALDHA1
D) ADH4 and ALDH1A1
E) ADH5 and ALDH2*2

Accepted Answer

The symptoms described are consistent with alcohol flush reaction, commonly associated with the ALDH2*2 allele, which leads to inefficient metabolism of acetaldehyde, a byproduct of alcohol metabolism. The ADH1B*1 allele is common in individuals who experience these symptoms.  Physiological responses to alcohol consumption are influenced by the activities of both the major ethanol-oxidizing ADH and the acetaldehyde-oxidizing ALDH isozymes. Because polymorphisms of ADH and ALDH2 play an important role in determining peak blood acetaldehyde levels and voluntary ethanol consumption, they also influence vulnerability to alcohol dependence. A fast ADH or a slow ALDH are expected to elevate acetaldehyde levels and thus result in rapid onset of undesirable side effects such as flushing, headache, and nausea. The ADH1B*1 allele has the highest rate of ethanol oxidation while the ALDH2*2 allele has little to no activity.

Question 9

Increased activity of which of the following alleles encoding enzymes of alcohol metabolism would be expected to have the greatest effect on the susceptibility to alcoholism?&#10;A) ADH1A&#10;B) ADH1B*1&#10;C) ADH1C*2&#10;D) ALDH2*2&#10;E) CYP2E1

Accepted Answer

Because polymorphisms of ADH and ALDH2 play an important role in determining peak blood acetaldehyde levels and voluntary ethanol consumption, they also influence vulnerability to alcohol dependence. A fast ADH or a slow ALDH are expected to elevate acetaldehyde levels and thus reduce alcohol drinking. The opposite would be expected such that individuals with slow ADH and normal or fast ALDH have a higher likelihood of alcoholism. Since the ADH1B*1 allele has the highest rate of ethanol oxidation, it would have the highest potential for an association with alcohol abuse. Although several CYP2E1 polymorphisms have been identified, only a few studies have been done to determine the effect on alcohol metabolism and tissue damage. In one study, the presence of the rare C-2 allele was associated with higher alcohol metabolism in Japanese alcoholics, but this effect was only seen at high blood alcohol concentrations. Individuals with the CYP2E1 RsaI polymorphism were shown to be more likely than others to abstain from alcohol consumption over their lifetimes

Question 10

Prolonged ethanol consumption and subsequent metabolism ultimately leads to a condition referred to as steatohepatitis or more commonly, "fatty liver syndrome." Ethanol metabolism results in alteration in the activity of which of the following enzymes, one of the consequences of which is excess lipid deposition in the liver?

A) fatty acyl-CoA oxidase
B) glucose-6-phosphate dehydrogenase
C) glycerol-3-phosphate dehydrogenase
D) lactate dehydrogenase
E) pyruvate dehydrogenase

Accepted Answer

Ethanol metabolism increases the NADH/NAD+ ratio, which enhances the activity of glycerol-3-phosphate dehydrogenase, leading to increased glycerol-3-phosphate and triglyceride synthesis, contributing to fatty liver.  The metabolism of ethanol by the liver leads to a large increase in NADH. This increase in NADH disrupts the normal processes of metabolic regulation such as hepatic gluconeogenesis, TCA cycle function, and fatty acid oxidation. Concomitant with reduced fatty acid oxidation is enhanced fatty acid synthesis and increased triglyceride production by the liver. In the mitochondria, the production of acetate from acetaldehyde leads to increased levels of acetylCoA. Since the increased generation of NADH also reduces the activity of the TCA cycle, the acetyl-CoA is diverted to fatty acid synthesis. The reduction in cytosolic NAD+ leads to reduced activity of glycerol-3-phosphate dehydrogenase (in the glycerol 3-phosphate to DHAP direction) resulting in increased levels of glycerol 3-phosphate, which is the backbone for the synthesis of the triglycerides. Both of these 2 events lead to fatty acid deposition in the liver leading to fatty liver syndrome and excessive levels of lipids in the blood, referred to as hyperlipidemia.

Deck 18: Ethanol Metabolism