Biochem 2-12 Alcohol Metabolism

Front 1

alcohol metabolism:

Back 1

EtOH
↓ ADH (or MEOS)
Acetaldehyde
↓ ALDH
Acetate

Front 2

Is EtOH metabolism oxidative or reductive? (Does it require NAD+ or NADH?)

Back 2

EtOH is oxidized to acetate which requires NAD+ as a reducing power.

Front 3

Does MEOS system produce NADH?

Back 3

nope

Front 4

Where is EtOH metabolized?

Back 4

mainly fed state liver; GI tract catabolizes small amount of EtOH; chronic alcoholism increases GI tract catabolism.

Front 5

What are the products of EtOH metabolism?

Back 5

acetate & NADH

Front 6

MEOS system

Back 6

With higher / chronic levels of ethanol consumption, MEOS catabolizes an increasing percentage of the ethanol to acetaldehyde.

Front 7

What enzyme converts acetaldehyde to acetate when the MEOS system is functioning?

Back 7

Acetaldehyde dehydrogenase (ALDH) catalyzes conversion of acetaldehyde to acetate in both systems. (MEOS & ADH systems)

Front 8

What enzyme converts EtOH→acetaldehyde in the MEOS system?

Back 8

CYP2E1, a cytochrome P450 enzyme

Front 9

What cofactor is required for CYP2E1?

Back 9

NADPH

Front 10

Since EtOH and NADPH get oxidized in the MEOS system, what is oxidizing agent?

Back 10

O2; NADPH + H + O2 → 2H2O; O2 is the oxidizing agent for all Cyt P450 enzymes

Front 11

EtOH inhibits _____.

Back 11

Other Cyt P450 systems. (other than MEOS)

Front 12

Who has a lower Km, CYP2E1 or ADH?

Back 12

ADH; ensures MEOS is induced as higher/chronic alcohol levels.

Front 13

What is the acetate produced from EtOH metabolism used for?

Back 13

activated to acetyl CoA for use in TCA, TG synth, ketone synth, and cholesterol synth

Front 14

Does activation of acetate to acetyl CoA require ATP?

Back 14

yup

Front 15

What must acetyl CoA be combined w/ for use in TCA?

Back 15

acetyl CoA + OAA → Citrate

Front 16

What is acetyl CoA converted to for TG synth?

Back 16

FAs

Front 17

How is the NADH produced from EtOH metabolism reoxidized?

Back 17

Ox-Phos and various dehydrogenase rxns

Front 18

Where is the acetate produced from EtOH metabolism used extra-hepatically?

Back 18

exported from liver and transported to heart, kidney & skeletal muscle

Front 19

How is the activity of ADH & ALDH controlled?

Back 19

by amount of EtOH in he blood

Front 20

What is the cause of abnormally high hepatic NADH levels due to high / chronic ethanol ingestion?

Back 20

NADH levels from high / chronic ethanol ingestion and catabolism may exceed the liver’s ability to reoxidize NADH via oxidative phosphorylation

Front 21

How is Ox-Phos regulated?

Back 21

by need for ATP vs. supply; Alcohol dehydrogenase and acetaldehyde dehydrogenase are not regulated by NADH/NAD+ or ATP/ADP-AMP levels. The amount of EtOH catabolism occurring depends on the amount of ethanol present.

Front 22

Excessive high hepatic NADH levels decrease what processes?

Back 22

TCA, β-oxidation, Glycolysis

Front 23

Excessive high hepatic NADH levels increase what processes?

Back 23

glycerol-3-phosphate production, lactate production from pyruvate & malate production from OAA

Front 24

How does EtOH metabolism cause fatty liver development?

Back 24

inreased glycerol-3-phosphate synth but decreased β-oxidation along w/ increased TG synth but decreased lipoprotein synth and export.

Front 25

How does EtOH metabolism contribute to ketoacidosis?

Back 25

In malnourished/fasted individuals, high NADH levels ↓ TCA which results in ↑ acetyl CoA levels; ↓ ketone utilization occurs because heart and kidney preferably catabolize acetate in preference to ketone bodies.

Front 26

How does EtOH metabolism contribute to lactic acidosis?

Back 26

↑ NADH levels ↑ pyruvate→lactate production; the liver imports less lactate for catabolism resulting in ↑ blood lactate levels

Front 27

How does lactate acidosis contribute to gout?

Back 27

Gout is caused by uric acid deposits in the joints; lactate compets w/ uric acid acid for kidney excretion.

Front 28

Why does hypoglycemia occur in fasted patients w/ high NADH levels?

Back 28

GNG is ↓ because tons of pyruvate from alanine transanimation is converted to lactate instead of glucose, reducing available alanine for GNG; Glycerol-3-phosphate is also not being converted to DHAP (opposite is occuring) further reducing GNG substrates available.

Front 29

How might hyperglycemia occur in a fed state due to high/chronic EtOH ingestion?

Back 29

high NADH levels ↓ hepatic glycolysis

Front 30

Why does acetaldehyde buildup to pathalogical levels w/ high/chronic EtOH ingestion?

Back 30

As ADH and MEOS' CYP2E1 activity increase, more acetaldeyde is produced than ALDH can process, leading to a buildup of acetaldehyde

Front 31

ALDH2

Back 31

alternative genotype of ALDH w/ lower activity than ALDH1

Front 32

Why is acetaldehyde buildup pathological?

Back 32

acetaldehyde binds to amino acids, decreasing protein synthesis Lipoprotein synthesis decreases due to lack of apoproteins, exacerbating fatty liver deelopment, aktering hepatocyte structure/funx

Front 33

How does acetaldehyde buildup lead to free radical formation?

Back 33

acetaldehyde binds gluathione, decreasing it's antioxidant capacity; ↑ CYP2E1 activity in the MEOS system also ↑ free radical formation

Front 34

Ethanol-induced hepatitis

Back 34

free radicals oxidize hepatic phospholipids and membranes, ↓ hepatic production of VLDL lipoproteins contributing to fatty liver

Front 35

ADH 4

Back 35

GI tract; catabolizes mainly excess EtOH relative to ADH 1& 2 capacity

Front 36

Which ALDH metabolizes most of the acetaldehyde from ADH, mitochondrail or cytolsic?

Back 36

mitochondrial; a common genetic variant of mitochondrial ALDH has low activity resulting in sickness with EtOH ingestion