• low molecular weight, water and lipid-soluble, nonprotonated – freely diffuses through lipid bilayers without osmotic effect
• it can be present in high concentration in body fluids
• 22 mM serum concentration = 0.10% = legally intoxicated
• 40-50 mM Þ alcoholic coma; there have been reports of levels as high as 100 mM
• alcoholic beverages also contain congeners that contribute to both behavioral and metabolic effects
• hundreds of compounds are distinct to each beverage; very little is known about them

Alcohol Dehydrogenase – primary method of ethanol metabolism

• net reaction: Ethanol + 2 NAD⁺ Þ acetate + 2 NADH + 2 H⁺
• oxidizes ethanol (CH₃CH₂OH) to acetaldehyde (CH₃CHO), producing NADH from NAD⁺
• another enzyme converts acetaldehyde to acetate, producing a second NADH
• present primarily in liver (also contains acetaldehyde dehydrogenase), also gastric mucosa to a small extent (more in males than females)
• High Affinity for Ethanol (K_M = 0.1 mM, less than 1% of intoxication concentration)
• zero-order kinetics at any appreciable concentration – oxidation rate is independent of concentration
• 7-100 mL/hr, depending upon body weight and functional liver mass
• This activity is probably an evolutionary response to presence of ethanol in portal circulation
• intestinal fermentation and ingestion of decaying foodstuffs produce concentrations of 0.05-0.10 (near K_M)
• thus, alcohol dehydrogenase prevents ingested ethanol from reaching other tissues
• Alcohol dehydrogenase can also act on methanol or ethylene glycol to produce toxic substances
• patients with methanol poisoning are given high doses of ethanol to overwhelm alcohol dehydrogenase
• rate of ethanol oxidation in liver is limited by reoxidation of NADH in respiratory chain
• Note: At high concentrations of ethanol (>10 mM), up to 20% may be oxidized by a second pathway, called the microsomal ethanol oxidation system (MEOS – in peroxysomes and microsomes), which converts ethanol + NADPH + O₂ Þ acetaldehyde + NADP⁺ + H₂O.

• Ethanol oxidation produces acetate Þ acetyl CoA and NADH, both of which are non-toxic sources of energy. Why is ethanol toxic?
• (1) Ethanol cannot sustain body weight
• ethanol provides about 10% of the energy of the average adult, up to 50% of heavy drinkers
• however, it cannot sustain body weight (1-2% weight loss if carbohydrates replaced with ethanol)
• (2) Ethanol produces too much NADH (dysregulated metabolism)
• normally, NADH level is tightly controlled, used by respiration (e^- transport chain) as fast as made by metabolism
• ethanol causes NADH overload, leading to metabolic disturbances and energy wasting
• alcoholic hypoglycemia – if drink in fasted state (8 hours after eating, when liver glycogen is depleted)
• need NAD⁺ for gluconeogenesis
• (1) 90% of gluconeogenesis is from amino acids via malate dehydrogeanse (malate + NAD⁺ Þ OAA)
• (2) 10% gluconeogenesis is from glycerol (lipolysis) via a -glycerophosphate dehydrogenase (glycerol-6P+NAD⁺Þ DHAP)
• (3) Cori cycle: lactate from muscles is also made into pyruvate via lactate dehydr. (lacate + NAD⁺ Þ pyruvate)
• high NADH/NAD⁺ ratio causes reduced rate of all of these, leading to hypoglycemia and coma
• amethystic therapy – speed up respiratory use of NADH, as occurs during hyperthyroidism or response to cold
• no harmless method discovered
• (3) Ethanol can produce ketosis (following alcohol-induced vomiting), even in non-diabetic individuals
• NADH overproduction converts acetate Þ acetyl CoA Þ b -hydroxybuterate, analogous to ketone body release from fatty acids
• (4) Ethanol metabolism produces free radicals
• both alcohol dehydrogenase and MEOS produce many free radicals, which can lead to liver damage
• (5) Ethanol alters function of membrane lipids and proteins
• e.g., integration into phospholipids alters function of neurotransmitter receptors
• acetaldehyde can also form adducts with long-lived proteins, altering their function