Alcohol Metabolism by alcohol dehydrogenase

1. Alcohol Metabolism by
alcohol dehydrogenases
By: Malvi Prakash (U53409030)

2. Ethanol Metabolism
• Ethanol is;
• Small 2-C molecule of alcohol, alcoholic hydroxy group
• Soluble in aqueous, lipid media. Thus, free passage into bodily
fluids
• Metabolised by 3 mechanisms:
• Alcohol dehydrogenase (ADH) – most important
• Microsomal ethanol oxidizing system
• Fatty acid ethyl ester synthase – non-oxidizing pathway
• Catalase (less significant)

3. Figure 1: Oxidative pathways of
alcohol metabolism: alcohol
dehydrogenase (ADH), CYP2E1,
catalase. Metabolism of alcohol. ADH,
present in the fluid of the cell (i.e.,
cytosol), converts alcohol (i.e.,
ethanol) to acetaldehyde. This reaction
involves an intermediate carrier of
electrons, + nicotinamide adenine
dinucleotide (NAD ), which is reduced
by two electrons to form NADH.
Catalase, located in cell bodies called
peroxisomes, requires hydrogen
peroxide (H2O2) to oxidize alcohol.
CYP2E1, present predominantly in the
cell’s microsomes. (1).

4. • Converted to acetaldehyde by alcohol dehydrogenase (ADH);
• ADH: homo- and heterodimers of α, β, γ sub-units
• high ethanol oxidation activity
• Acetaldehyde: highly unstable, toxic, destroy embryonic neural crest cells,
birth defects, liver and kidney damage
Ethanol Metabolism Contd…

5. … is then converted into acetic acid by alcohol dehydrogenase 2
acetic acid converted to acetyl-CoA by acetyl CoA synthase 1 and 2
acetyl CoA converted to CO2 and H2O through citric acid cycle
Ethanol Metabolism Contd…

6. Figure 2: The Basic Pathways (2)

7. Ethanol Metabolism Contd…
• Microsomal Ethanol Oxidation System (MEOS)
• Contains CYP450 (CYP2E1, CYP1A2, CYP3A4) which oxidizes
ethanol
• Chronic alcoholics
• Metabolism by CYP2E1 (Figure 3):
• leads to conversion of NSAID acetaminophen into toxic metabolites
• Release of free radicals
• Acetaldehyde production, low reduced GSH, high oxidant effects,
hepatocyte damage
• Lipid hydroperoxides: NAFLD, non-alcoholic steatohepatitis, NASH
associated with hyperlipidemia, obesity, type 2 diabetes

8. Figure 3: Mechanism of
ethanol metabolism by MEOS

9. • Reduced blood sugar
• Oxidation reactions by ADH and ALDH result in NADH/NAD+ cellular
imbalance
• Reduced NAD+ impairs glucose influx at glyceraldehyde, 3- phosphate
dehydrogenase via glycolysis, low energy production
• NADH must reconvert to NAD+ by either malate-aspartate shuttle or
glycerol phosphate shuttle
Outcomes of the metabolism

10. • Reduced blood sugar continued
• Hepatocytes function these shuttles and thus give the capability of a
person to metabolize ethanol affected by TCA cycle in
mitochondria which is negatively affected by high NADH production
• High NADH increases hepatic lactate in LDH reaction diverts
pyruvate from gluconeogenesis low glucose delivery to blood by
liver
Outcomes of the metabolism

11. • Hypoxia
• NADH by ADH and ALDH is oxidized in mitochondria by oxidative
phosphorylation, requires O2
• Hepatocytes near O2 rich arteries take up extra O2 less O2 for liver
• Hypoxia in perivenous hepatocytes reported
• Increases O2 consumption of Kupffer cells release prostaglandin
increasing activity of hepatocytes more O2 consumption
Hypoxia
• Acetaldehyde-lysine adducts create immune response by antibody
production leading to immune system – mediated destruction off
hepatocytes (ADCC) and liver damage
Outcomes of the metabolism

12. Effects of NAD+/NADH Ratio Fluctuation

13. • Acetaldehyde – erythrocyte membrane adducts associated with
ethanol – induced macrocytosis
• ethanol – induced macrocytosis: high numbers of enlarged
erythrocytes in blood marker abuse of alcohol
• Acetaldehyde – biogenic anime adducts like with
neurotransmitters (dopamine, serotonin) adverse effects on
nervous system
• Increased ROS leading to cancer development, atherosclerosis,
diabetes, inflammation, aging, and other harmful processes
(Figure 4)
Outcomes of the metabolism

14. Figure 4: Metabolism outcomes

15. Methanol Metabolism
• Methanol;
• Absorbed via skin, inhalation, ingestion
• Produces anion gap metabolic acidosis, CNS and ocular toxicity,
putaminal necrosis
• Usage of alcohol dehydrogenase inhibitors
• Used as antifreeze, carburetor fluid, duplicator fluid, inks, gasohol,
dry gas, adhesives, formalin, embalming fluid precursor for
plastics, films and dyes

16. Methanol Metabolism Contd…
• Is converted to formaldehyde by alcohol dehydrogenase
• Does not accumulate
• Is converted to formic acid
• Slow metabolism, accumulation
• Primary toxicant
• Formic acid is converted to formate by aldehyde dehydrogenase and
H+ ion
• Which is further metabolized to CO2 and H2O by folate-dependent
mechanism

17. Outcomes of the metabolism
• Formic acid inhibits mitochondrial cytochrome oxidase
prevention of oxidative metabolism tissue hypoxia
• Formic acid and lactic acid formation cause systemic acidosis
production of undissociated formic acid movement of methanol
across cell membrane into CNS
• Formic acid raises early anion gap metabolic acidosis which disrupts
normal cellular development leading to lactic acidosis

18. Outcomes of the metabolism
• Oedema, necrosis of basal ganglia, hemorrhage in subcortical white
matter
• Putamen, because it uses more oxygen and glucose, is the most
vulnerable to the effects of methanol poisoning
Acidosis Movement of formic
acid into cells
Reduction of
undissociated formic
acid
Ocular toxicityUndissociated formic acid targets optic disc

19. Treatment Goals
• Bicarbonates for acidosis
• ADH inhibitors that convert methanol into toxic compounds like
fomepizole (Antizol)
• Side effects of fomepizole include headache, nausea, rashes, eosinophilia,
inflammation at site of infusion, dizziness, mild and reversible transaminase
elevation
• Hemodialysis to remove parent alcohol and its metabolites
• Folinic acid

20. Figure 5: Stages of Methanol
Poisoning (9)

21. Ethylene Glycol Metabolism
• Ethylene Glycol;
• Used as antifreeze agent and in fluorescein dye
• Faster metabolism than methanol
• Initial toxication stages might be asymptomatic but is eventually
symptomatic by altered mental status and dyspnea
• Early symptoms: intoxication, nausea, abdominal pain
• Later symptoms: unconsciousness, seizures, headache
• Long term: brain damage, kidney failure
• Fatal

22. Ethylene Glycol Metabolism Contd…
• Ethylene glycol is converted to glycolaldehyde by alcohol
dehydrogenase
• glycolaldehyde is converted to glycolate, which is responsible
for acidosis and poisoning
• Glycolate metabolism has various pathways one of which
converts it to oxalate which rapidly precipitates with calcium
• Other mechanisms are explained in figure 6

23. Ethylene Glycol Metabolism Contd…
Figure 6: Ethylene Glycol
Metabolism schematic diagram
(11)

24. Outcomes of the metabolism

25. Summary
Figure 7: Summary of
ethanol, methanol,
ethylene glycol
metabolism

26. Thank You