Ethanol Metabolism

acetaldehyde, cytosolic alcohol dehydrogenase (ADH)

In the liver, ethanol is oxidized to __ by __ and generates NADH.

acetate

mitochondrial aldehyde dehydrogenase (ALDH)

Once ethanol is oxidized to acetaldehyde, it enters the mitochondria and is oxidized to — by —, generating NADH.

acetyl CoA

acetyl CoA synthetase

Once ethanol is metabolized to acetate, it is activated to — by —

fatty acids, cholesterol

Once ethanol is metabolized to acetyl CoA, it is used for the synthesis of — or — in the liver.

ALDH1: cytosolic, high Km for acetaldehyde

ALDH2: mitochondrial, low Km for acetaldehyde

Differences between the two isozymes of aldehyde dehydrogenase in hepatocytes

East-Asian populations (~40%) possess an allelic variant of ALDH2 (ALDH2*2), that has 100-fold higher Km than ALDH2.

Higher Km leads to acetaldehyde buildup (20-30-fold) before cytosolic ALDH1 or ALDH2*2 can metabolize acetaldehyde.

These individuals have an adverse reaction to ethanol due to the build-up of acetaldehyde (a toxic metabolite) in the tissues and serum. 

This leads to general vasodilation (characterized by facial flushing) and tachycardia, nausea, and dizziness.

Variant of ethanol metabolism common in East Asian populations

Induced by chronic ethanol consumption. Increases rate of alcohol clearance and the rate of acetaldehyde production, which increases risk of hepatocyte injury.

Microsomal Ethanol Oxidizing System: induction and effects

Chronic ethanol consumption induces CYP2E1, which converts acetaminophen to toxic intermediate NAPQI, which binds to sulfhydryl group of proteins and causes liver damage

How alcohol interacts with acetaminophen

amino groups, sulfhydryl groups, nucleotides and phospholipids

“adducts”

Acetaldehyde is highly reactive and binds to — to form —

alcohol-induced hepatitis

Acetaldehyde-adduct decreases the protein synthesis in the liver and contributes towards the development of —.

glutathione

Acetaldehyde-__ adduct formation increases free radical damage

Inhibits fatty acid oxidation

Induces ketoacidosis

Causes lactic acidosis

Leads to hyperlipidemia and fatty infiltration in liver

Inhibits gluconeogenesis

Ethanol metabolism increases NADH levels. Consequences?

malate, acetyl CoA

High NADH/NAD ratio inhibits isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase and malate dehydrogenase. This shifts the oxaloacetate to — and inhibits the oxidation of —.

fatty acids, triglyerides

Inhibition of fatty acid oxidation by ethanol (resulting high NADH) leads to accumulation of — and increased synthesis of — in the liver

glycerol 3-phosphate, triglycerides

High NADH promotes the conversion of DHAP to —, and its esterification to fatty acyl CoA leading to the synthesis of —.

lactate, hypoglycemia

High levels of NADH inhibits the conversion of lactate, alanine and glycerol to glucose

High NADH inhibits gluconeogenesis, increases —, and leads to —.

Because?

Decreases the excretion of uric acid by kidney leading to the development of hyperuricemia and Gout

Uric acid excretion “competes” with lactic acid excretion

Effect of elevated NADH/NAD ratio in the kidney

formaldehyde, formate

blindness, CNS depression, severe metabolic acidosis

Methanol is metabolized by ADH to — then ALDH converts it to —. These symptoms:

glycolate,

brain, heart, and kidneys

Ethylene glycol metabolized to glycoaldehyde and then — then oxalate; the latter two responsible for toxic effects in —(3)

Alcohol directly inhibits the expression and function of thiamine transporters (e.g., THTR-1 and THTR-2) in the intestinal lining, impairing absorption.

One way that alcohol leads to thiamine deficiency