Alcohol Metabolism

Question 1

Why does oral ingestion lead to lower blood ethanol level than IV

Answer 1

First pass metabolism in the stomach but mostly in the liver (80-85%)

Question 2

Excretion of unmetabolised alcohol

Answer 2

3-10% breath, urine and sweat

Question 3

BAC

Answer 3

detectable within 5 mins and max after 30-90 mins.

effect of -Oh = concentration and duration of exposure

Question 4

Three alcohol metabolism pathway

Answer 4

Main = ADH
Peroxisome pathway by catalase
Microsomes pathway with CYP2E1
ALDH2 = second, common pathway

Question 5

ADH pathway details

Answer 5

Alcohol –> acetaldehyde (via ADH) and then Acetaldehyde to Acetate (via ALDH)

Question 6

Expressive drinking is accumulation of

Answer 6

toxic acetaldehyde

because 3 pathway leading to this stage but then only one ahead

Question 7

ADH class mainly responsible for alcohol metabolism

Answer 7

Class I ADH in liver

Question 8

Class of ADH recruited in chronic or heavy drinkers

Answer 8

Class III ADH

Question 9

Class of ADH in gastric mucosa

Answer 9

Class IV

Question 10

Acetaldehyde metabolism

Answer 10

predominantly ALDH2

Question 11

Asian flush

Answer 11

ALDH 2*2 genetic polymorphism - reduce rate of metabolism

Question 12

Microsomal Ethanol Oxidizing system (MEOS)

Answer 12

Ethanol + NADPH + H + O –> acetaldehyde + NADP + water
catalysed by microsomal cytochrme P450 2E1
increased 4-10 folds in chronic or large -OH consumption

Question 13

significance of CYP 450 use in chronic and large alcohol consumption

Answer 13

used for drug metabolism, increased actitivty = beneficial for detoxification but also harmful because you get heptotoxicity from drugs

Question 14

When is MEOS pathway utilised

Answer 14

large/chronic -OH consumption.
low affinity to ethanol vs high affinity hepatic ADH.
Can occur in Brain

Question 15

Catalase-mediated alcohol oxidation

Answer 15

Marginal pathway in liver except fasted state
fatty acids –> hydrogen peroxide, then thats used with catalase to make acetaladehyde
MAJOR IN BRAIN (b/c ADH not physiologically active in brain)

Question 16

Non-oxidative pathway

Answer 16

high BAC
Fatty acid ethyl ester (FAEE) in chronic alcohol abuse –> steatosis –> alcoholic pancreatitis (in pancreas, low ADH so use non-oxidative pathway more)

Question 17

Mechanism for beneficial effect of alcohol consumptions

Answer 17

Resveratrol

• anti-oxidant
• anti-thrombotic : inhibit thromboxane synthesis and platelet aggregation, increase vasodilatory prostacyclin synthesis
• inhibit oxidation of LAL cholestrol and increase HDL cholestrol

Question 18

Tissue damage in excessive drinking caused by

Answer 18

Acetaldehyde

Question 19

Physiological effects of excess acetaldehyde

Answer 19

“alcohol sensitivity” in periphery

• facial flushing, throbbing in head and neck
• headache, nausea, vomiting
• sweating, thrist, chest pain, palpitation
• dyspnea, hyperventilation, tachycardia
• hypotension, syncope, marked uneasiness
• weakness, vertigo, blurred vision, confusion

Question 20

Health effects of heavy -OH use

Answer 20

Thiamin deficiency
Vit B6 and folate deficiency
increased disease risk
malnutrition

Question 21

How does excess alcohol cause liver injury

Answer 21

Chronic alcohol - increases gut permeability which increase endotoxin from gram -ive bacteria entering this activates kupffer cells in liver which then released cytokines (like TNFa) and ROS which lead to inflammatory response, oxidative stress and activation of hepatic stellate cell

Question 22

Role of hepatic stellate cell in liver dibrosis

Answer 22

in normal cells , HSC = store Vit A and maintain ECM like collagen and regulate BF
activated in liver injury by Kupffer cells –> increase cell proliferation and migration and increase collagen type 1 synthesis which leads to liver scarring and fibrosis

Question 23

3 pathways leading to detrimental effects of alcohol oxidation

Answer 23

1. acetaldehyde adduct formation
2. Increase ROS formation
3. Increase NADH:NAd ratio

Question 24

Acetaldehyde adducts

Answer 24

Excess acetaldehyde combined with DNA, lipid or protein can induce immune response that leads to liver damage

Question 25

Sources of oxidative stress

Answer 25

1. Due to increase MEOS CYP2E1 - which leads to production of ROS 2. due to excess NADH, which is oxidised to NAD and causes O2 to go to O2 -ive

Question 26

Excess NADH formation

Answer 26

Alters NADH and NAD ration - changes carb and lipid metabolism - redox state, --> hypoxia --> liver damage

Question 27

why can't be metabolise glucose in excess NADH formation

Answer 27

inhibition of TCA cycle

Question 28

Result of NADH excess and altered glucose metabolism

Answer 28

- no gluconeogenesis, --> depletion of glycogen stores --> hypoglycemia - increase lactate --> lactic acidosis

Question 29

Lipid metabolism nd NADH excess

Answer 29

can't enter citric cycle as Acetyl CoA | reduced FA metabolism and increase FA synthesis

Question 30

Result of NADH excess and altered lipid metabolism

Answer 30

excess FA and acetyl CoA accumulates in liver --> alcohol induced ketosis --> fatty liver and alcoholic steatosis

Question 31

Effect of acute alcohol ingestion on NT

Answer 31

``` - inhibit excitatory glu NT agonist for GABA a thus - - increase GABA release also - increase 5-HT - activate opioids and - - cannabinoid R increase DA release ```

Question 32

Dry beri beri

Answer 32

peripheral neuropathy

Question 33

Wet beri beri

Answer 33

congestive heart fail

Question 34

Effects of Thaimine deficiency

Answer 34

Beriberi = lesion in PNS | Wenicke-Korsakoff syndrome - lesions in CNS

Question 35

Some features of Wernicke's encephalopathy

Answer 35

- gait ataxia (lack of coordination) - ophthalmoplegia (eye nerve paralysis) - mental confusion/memory loss

Question 36

Treatment of wernicke's encephalopathy

Answer 36

IV B-vitamin complex

Question 37

Korsakoff

Answer 37

chronic debilitating amnesia

Question 38

Role of Thaimine

Answer 38

1. important in cellular reactions - pentose phosphate pathway, glycolysis, citric acid cycle 2. imp in carb --> energy 3. critical in CNS function - synthesis of Ach and GABA

Question 39

pathway for brain damage in alcoholics

Answer 39

1. altered cerebral energy metabolism 2. oxidative stress and inflammation 3. impaired NT function

Question 40

Which alcohol metabolism pathway happens in the mitocondria

Answer 40

Acetaladehyde --> acetate via ALDH2

Question 41

Which alcohol metabolism pathway happens in the cytosol

Answer 41

Ethanol --> acetaladehyde via ADH

Question 42

Which alcohol metabolism pathway happens in the Perisomes

Answer 42

Ethanol --> acetaladehyde via Catalases

Question 43

Which alcohol metabolism pathway happens in the Microsomes

Answer 43

Ethanol --> acetaladehyde via CYP2E1 MEOS pathway