Drinking as a Liefstyle Case Sep 17

Question 1

After consumption, in what tissues does ethanol partition? What tissues exclude ethanol?

Answer 1

Ethanol is absorbed through the GI system (especially the small intestine) into the blood.

THe blood will first enter the hepatic portal vein where the liver will udnergo first pass metabolism of the ethanol

After that, the ethanol will be distributed to all tissues

It partitions into acqueous areas - tissues with a lot of water will have a lot of ethanol

It’s excluded from areas that do not have water, specifically fat tissue and bone.

(this is why females will get drunker faster - they have higher fat content, so less area over which the ethanol can be spread)

Question 2

What is the primary pathway by which ethanol is metabolized? WHat are the products of this?

Answer 2

Ethanol is broken down by aldohol dehydrogenase into acetaldehyde, convertin NAD to NADH.

Adetaldehyde is converted to acetate using acetaldehyde dehydrogenase and NAD to NADH.

Acetate can be acted on by acetyl CoA synthetase (hydrolyzing ATP to ADP) for form acetyl CoA.

Acetyl CoA can either be used in fatty acid synthesis by the liver, or enter the TCA cycle in muscles.

Question 3

What is the secondary pathway for ethanol metabolism? WHy does it only occur at higher concentrations of ethanol?

Answer 3

The Microsomal Ethanol Osidizing System (MEOS)

THrough this pathways, CYP2E1 convers ethanol to adetaldehyde through a cytochrome pathway, which converts NADPH to NADP and uses O2 as the ultimately electron acceptor.

After that, ALDH will work on the acetaldehyde as in the primary system, so the produces are NADH and acetyla CoA ( you get less energy production thorugh because you lose the NADPH)

THis will only occur at higher concentrations of ethanol because CYP2E1 has a higher Km than ADH.

Question 4

How do inherited mutations in ethanol metabolizing enzymes alter carriers’ susceptibility to alcoholism?

Answer 4

Mutations in ADH often make if more active, meaning ethanol will be converted to adetaldehyde much faster.

People with mutations like this will become MUCH sicker off of a smaller amount of alcohol and are therefore less likely to become alcoholics.

Mutations in ADLH that make it more active are found in people who can drink heavily without getting hangovers.

Question 5

What drug is often used in an attempt to help someone overcome alcoholism?

Answer 5

disulfiram

Question 6

WHat is the mechanism of action for disulfiram?

Answer 6

The drug is able to compete with the NAD for binding sites on aldehyde dehydrogenase. This means that people taking the drug will experience a much higher concentraiton of acetaldehyde off of a much smaller amount of alcohol. This makes them sick in the hopes that they’ll be turned off alcohol.

It’s not super effective unfortunately.

Question 7

What are the kinetics for ALDH in the presence and abscence of disulfiram?

Answer 7

DIsulfiram acts as a competitive inhibitor of ALDH.

The Km of ALDH is higher in the presence of disulfiram, making it a less active enzyme. The Vmax would not change, however.

Question 8

What off-target enzyme does disulfiram also inhibit?

Answer 8

Dopamine hydrosylase, which converts dopamine to norepinephrine.

Question 9

Where in the cell do the following aspects of alcohol metabolism occur?

ADH

ALDH

CYP2E1

catalase

Answer 9

ADH : cytosol

ALDH : Mitochondria

CYP2E1 : Microsomes

catalase: peroxisomes (less important)

Question 10

What receptors does norepinephrine activate? WHat types of cells express this receptor?

Answer 10

alpha-adrenergic receptors on smooth muscle

beta-adrenergic receptors on the heart

Question 11

What is the signalling pathway when norepineprhine binds the alpha adrenergic receptor?

What is the signalling pathway when norepinepthrin binds the beta adrenergic receptor?

Answer 11

alpha: activates phopholipase C which cutes IP2 into IP3 and DAG. DAG activates PKC and IP3 activates calcium, both of which will activate calmodulin kinase and leave to smooth muscle constriction.
beta: activate adenylyl cyclse to increase cAMP

Question 12

Why would dopamine not have been effective in treating the patient’s hypotension in the ER?

Answer 12

THe disulfiram is still in his system so it is still blocking the dopamin hydroxylase reaction so dopamine isn’t converted to norepinephrine, which is the hormone necessary to increase blood pressure.

Question 13

When at the catecholamines released?

WHat is their role?

Answer 13

catecholamines:

Act as both neurotransmitters and circulating hormones

Secreted in response to pain, hemorrhage, exercise, hypoxia and hypoglycemia

Activate the fight or flight response
increased cardiac output
mobilization of fuel stores

Question 14

How is serum triglyceride homeostasis hormally maintained?

Answer 14

Glucagon and insulin regulate hormone sensitive lipase within the adipose tissue. Glucagon in the fasted state will mobilize the stored fuels. The liver packages synthesized triglycerides into VLDLs to transport thorugh the blood.

Question 15

How does ethanol metabolism contribue to triglyceride production?

Answer 15

It produces acetyl CoA, which can be used for fatty acid synthesis and triglyceride production.

Question 16

Why didn’t the patient experience an associated increase in cholesterol in the blood when triglycerides were increased?

Answer 16

Normally, cholesterol would also increase because the excess triglycerides would need to be stored in lipoproteins in the blood, which need cholesterol for their membranes.

However, because ethanol metabolism increases NADH, beta oxidation of fatty acids will be inhibited because it reuquires NAD+. The storage pathway is also inhibited by the increase in acetyl CoA.

This means that the excess triglycerides in the blood are all dietary from the alcohol and have no fate–they’re not burned and they’re not stored.

They’re just hanging out in chylomicrons in the plasma

CHylomicrons have the lowest cholesterol levels of all the lipoporotesin, so you don’t see the increase in cholesterol synthesis.

Question 17

How does alcoholism lead to fatty liver?

Answer 17

The increased NADH/NAD ratio means beta oxidation of fatty acids is inhibited. Dietary fatty acids are therefore stored, not oxidized for fuel.

THe excess fatty acids to be stored will bulid up to some extent in the liver.

Question 18

What affect does the increased NADH/NAD ratio from ethanol metabolism have on the TCA cycle? Glycolysis?

Answer 18

Pyruvate will be directed towards lactate synthesis rather than acetyl CoA, resulting in lactic acidosis.

Acetyl CoA will be directed towards ketone body synthesis rather than citrate synthesis, leading to ketoacidosis.

Question 19

Why does hypoglycemia occur in the fasted state for alcoholics?

Answer 19

Since the TCA cycle was inhibited with acetyl CoA directed towards ketone bodies and pyruvate directed toward lactate, there is no TCA cycle intermediates available for gluconeogensis and you get hypoglycemia

Question 20

How is the increase in acetaldehyde in ethanol metabolism linked to actual disease (not just hangover symptoms)?

2 ways

Answer 20

1. Acetaldehyde is a reactive molecule which can bind DNA and proteins to form adducts which interfere with mitochodnrial metabolism, DNA repair, and DNA replication.

FOr example, acetaldehyde can impair the function of tubulin. Vesicles filled with proteins after modification in the GOlgi will transport the proteins by traveling along the tubilin to the plasma membrane. If there is damage to the tubulin because of the aldehyde adducts, tubulin polymerization is inhibited and the vesicles can’t transport their contents to the membrane. Thus, they build up in the hepatocytes. Water then flows into the hepatocytes to counteract the osmolarity and you get reupture of the individual cells and swelling of the liver.

2. Acetaldehyde also leads to increased exposure to ROS.

It binds and activates glutathione, an important sink for ROS.

It also forms adducts on mitochondrial proteins and uncouples the ETC, leading to increased ROS producion and further damage of mitochondrial enzymes like ALDH2, preventing ocnversion of adetaldehyde to acetate, leading to a vicious cycle.

Question 21

How does the MEOS pathway contribute to disease in alcoholism?

Answer 21

Incomplete conversion of ethanol to acetaldehyde through MEOS can result in release of the hydroxyethyl radical, CH3CH2O.. The hydroxyethyl radical can cause peroxidation of membrane lipids, resulting in damage to plasma and mitochondrial membranes.