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Flashcards in Alcohol Metabolism Deck (43):
1

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

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

2

Excretion of unmetabolised alcohol

3-10% breath, urine and sweat

3

BAC

detectable within 5 mins and max after 30-90 mins.
effect of -Oh = concentration and duration of exposure

4

Three alcohol metabolism pathway

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

5

ADH pathway details

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

6

Expressive drinking is accumulation of

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

7

ADH class mainly responsible for alcohol metabolism

Class I ADH in liver

8

Class of ADH recruited in chronic or heavy drinkers

Class III ADH

9

Class of ADH in gastric mucosa

Class IV

10

Acetaldehyde metabolism

predominantly ALDH2

11

Asian flush

ALDH 2*2 genetic polymorphism - reduce rate of metabolism

12

Microsomal Ethanol Oxidizing system (MEOS)

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

13

significance of CYP 450 use in chronic and large alcohol consumption

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

14

When is MEOS pathway utilised

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

15

Catalase-mediated alcohol oxidation

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)

16

Non-oxidative pathway

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

17

Mechanism for beneficial effect of alcohol consumptions

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

18

Tissue damage in excessive drinking caused by

Acetaldehyde

19

Physiological effects of excess acetaldehyde

"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

20

Health effects of heavy -OH use

Thiamin deficiency
Vit B6 and folate deficiency
increased disease risk
malnutrition

21

How does excess alcohol cause liver injury

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

22

Role of hepatic stellate cell in liver dibrosis

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

23

3 pathways leading to detrimental effects of alcohol oxidation

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

24

Acetaldehyde adducts

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

25

Sources of oxidative stress

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

26

Excess NADH formation

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

27

why can't be metabolise glucose in excess NADH formation

inhibition of TCA cycle

28

Result of NADH excess and altered glucose metabolism

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

29

Lipid metabolism nd NADH excess

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

30

Result of NADH excess and altered lipid metabolism

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

31

Effect of acute alcohol ingestion on NT

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

32

Dry beri beri

peripheral neuropathy

33

Wet beri beri

congestive heart fail

34

Effects of Thaimine deficiency

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

35

Some features of Wernicke's encephalopathy

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

36

Treatment of wernicke's encephalopathy

IV B-vitamin complex

37

Korsakoff

chronic debilitating amnesia

38

Role of Thaimine

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

39

pathway for brain damage in alcoholics

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

40

Which alcohol metabolism pathway happens in the mitocondria

Acetaladehyde --> acetate via ALDH2

41

Which alcohol metabolism pathway happens in the cytosol

Ethanol --> acetaladehyde via ADH

42

Which alcohol metabolism pathway happens in the Perisomes

Ethanol --> acetaladehyde via Catalases

43

Which alcohol metabolism pathway happens in the Microsomes

Ethanol --> acetaladehyde via CYP2E1 MEOS pathway