biochem 2: ethanol metabolism

ethanol is small and readily soluble in both

water and lipids

ethanol is absorbed in ____ via ____

digestive tract by passive diffusion

Approximately _____ of ingested ethanol is metabolized by the liver

90%

the remainder is metabolized by cells of

GI tract or breast tissue, or excreted

ethanol can have adverse effects on

GI tract

ethanol decreases intestinal absorption of ____ and ____

intestinal absorption of AA and some vitamins

heavy consumption of alcohol may result in damage to _______, resulting in _____, _____ and/or increased ____ to toxins.

mucosal cells, resulting in erosion, bleeding, and/or increased permeability to toxins.

primary nutritional deficiencies w/ alc consumption - ethanol contains _____ of empty calories. alcohol can often consume _______.

ethanol contains 4.5-7kcal/g of empty calories. alc can often consume nutrient deficient diets, as most of their calories are from alc

secondary nutritional deficiencies with alc consumption

ethanol impairs absorption and/processing of

essential AA and FA

vitamin B1, B2, B6, C, folic acid, vitamin A (retinoic acid)

Ethanol is converted to _____ and then ______. ____ is converted to _____ and used as fuel for ______ and ______

acetaldehyde, and then acetate. Acetate is converted to acetyl CoA and used as a fuel for skeletal and heart muscle.

Unpleasant effects of ethanol consumption (flushing, nausea, etc.) are due to

acetaldehyde

Acetaldehyde is highly reactive; it generates ____ and binds to _____. toxicity contributes to development of ______ and _____ in the liver

ROS and binds to proteins. Toxicity contributes to development of inflammation and steatosis in the liver.

acetaldehyde is converted to ____ by _____

acetate by acetaladehyde dehydrogenase

Two enzyme systems are responsible for converting ethanol to acetaldehyde:

alcohol dehydrogenase (ADH)

microsomal ethanol oxidizing systems

major route of ethanol metabolism in the liver is via

alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)

ADH exists as a family of isozymes with varying ______. generally, the Km values are _______

kinetic parameters for ethanol. Generally, the Km values are quite low.

ALDH exists as a ______ with a very high affinity to ______, and a cytosolic isozyme with a much lower ________

exists as a mitochondrial isozyme with a very high affinity for acetaldehyde and a cytosolic isozyme with a much lower affinity for acetaldehyde

polymorphisms in ADH and ALDH greatly affect the rate of

ethanol metabolism and/or accumulation of acetaldehyde in individuals

ethanol --> acetate

Ethanol is also oxidized to acetaldehyde by MEOS, which involves ______, primarily _____, in the ________

cytochrome P450 enzymes (primarily CYP2E1) in the hepatic endoplasmic reticulum

______ is the primary P450 in the MEOS, which is composed of additional P450s as well as corresponding cytochrome P450 reductases

CYP2E1

The Km for the MEOS system toward EtOH is

higher than that of ADH.

Furthermore, CYP2E1 expression is induced

by EtOH.

Therefore, the MEOS system plays important roles when

a person drinks heavily and/or frequently.

MEOS

alcohol induced liver disease begins with either _____ or _____. either is ____, but may progress to ______ and eventually _______

steatosis (fatty liver) or alcohol induced hepatitis (inflammation) reversible but may progress to hepatic fibrosis and eventually cirrhosis

90% of men who drink more than ______ and women who drink more than _____ will develop fatty liver

60g/d

40g/d

hepatitis, fibrosis, or cirrhosis will develop in

40% of those who have alcoholic fatty liver

stages of liver disease

fatty liver - deposits of fat cause liver enlargement

liver fibrosis - scar tissue forms

cirrhosis - growth of connective tissue destroys liver cells

ADH and ALDH consume _____ and produce ______

NAD+ and produce NADH during ethanol metabolism.

The resulting high NADH/NAD+ alters

hepatic metabolism of other fuels.

consequences of high hepatic NADH/NAD+

1. Beta oxidation of fatty acids is inhibited

2. TCA cycle is inhibited

3. Lactate cannot be converted to pyruvate in the liver

1. beta oxidation of fatty acids is inhibited - fatty acids will accumulate in the _____ and re-esterify to _____. some remain trapped in liver, resulting in _____ and others are incorporated into VLDL, contributing to ______

Fatty acids accumulate in the liver, and are re-esterified to TAG. Some remain trapped in the liver, resulting in steatosis, and others are incorporated into VLDL, contributing to hyperlipidemia.

2. TCA cycle is inhibited: _____ accumulates in hepatocytes and is converted to _____. because extra-hepatic tissues are using acetate for fuel, they will not use the _____, and ____ may result.

Acetyl-CoA accumulates in hepatocytes and is converted to ketone bodies. Because extrahepatic tissues are using acetate for fuel, they will not use the ketones, and ketoacidosis may result (Alcoholic ketoacidosis)

3. Lactate cannot be converted to pyruvate in the liver - The lactate dehydrogenase reaction

will not favor pyruvate formation in the liver.

Furthermore, gluconeogenesis from glycerol and oxaloacetate

is also inhibited.

This results in _________. Lactic acidosis can result in _______ as the kidney’s capacity to eliminate uric acid is impaired.

lactic acidosis and hypoglycemia; lactic acidosis can result in hyperuricemia

Acetaldehyde is highly reactive; it generates

ROS and binds to proteins.

acetaldehyde toxicity contributes to development of

inflammation and steatosis in the liver.

Decreased serum protein synthesis →

Edema, Ascites, & Poor blood clotting

Impaired amino acid uptake →

Elevated serum amino acids, esp. In catabolic state

Decreased urea cycle function →

Hyperammonia, Encephalopathy

Inefficient bilirubin glucuronidation→

Jaundice

Hepatocyte injury/death, resulting in release of enzymes to serum →

Elevated serum AST, ALT, and Alkaline phosphatase.

ingested alcohol is completely metabolized within

8-12 hours, but physical effects can last longer

physical effects of hangover

dehydration

hypoglycemia and lactic acidosis

GI irritation

acetaldehyde

EtOH is an

diuretic

GI irritation with alcohol -

increased gastric acid

gastritis

acetalaldehyde is a

potent vasodilator

causes headache, trembling, ill feeling

potent vasodilator -

causes flushing seen in some individuals after EtOH consumption

the amount of volatile substances, such as ______ and ______ in alcoholic beverages correlates to ______

methanol and fusel oils, severity of hangover