Integration 1: Alcohol Metabolism Flashcards
Where does fermentation occur?
- fruits
- bacteria
- yeasts
- fungi
- mammalian muscle
fermentation vs. glycolysis vs. cellular respiration
Describe ethanol
C2H5OH is a small, volatile, water and lipid soluble molecule that easily diffuses across membranes
* dietary component that is consumed but not a nutrient
* 7 kcal/g ‘empty calories’
* up to 10% of kcals in normal diet, 50% in chronic alcoholics
* not stored and no “natural” level in the body
* structurally similar to CHO but metabolized more like lipids to acetyl CoA with RQ of 0.66 and metabolized to acetyl CoA
How is ethanol absorbed and digested?
Absorbed by rapid diffusion through the GI tract and requires no digestion
* mostly SI, about 20% in stomach
What is the rate of ethanol absorption?
about 20 min but rate can depend on food intake which acts as a barrier, alcohol concentration, how much you take in.
Where does ethanol metabolism happen?
primarily liver which has 1st pass, some in the stomach, very little in other tissues
How have humans evolved to metabolize alcohol?
evolved to express genes & isoforms to detoxify alcohol
* ethanol consumption for 1000s of years as beverage but also naturally occuring fruits
* different isoforms of the gene are required to metabolize conusmed alcohols & produced by intestinal microflora
What is the rate of alcohol metabolism?
metabolism (clearance) is slower than absorption being ~0.5oz/h of pure alcohol (~1beer)
What are the 3 pathways used to detoxify/metabolize alcohol?
- ADH (constitutive)
- MEOS (inducible)
- Catalase (minor)
What is the ADH pathway
Alcohol dehydrogenase which is the major pathway and can metabolize 80%.
* Mostly occurs in the cytosol of hepatocytes, some in gastric cells
* Used in small amounts (reccomended) of alcohol
* rate of ~0.5 oz/hr
What are the steps of the ADH pathway?
- ADH metabolizes ethanol → acetaldehyde using NAD+ & generating NADH + H+
- Acetaldehyde build up → acetic acid requires ALDH (aldehyde dehydrogenase) which needs NAD+ and generates more NADH and H+
- Final step is acetic acid + coenzyme A to form acetyl-CoA (enters mitochondria and TCA cycle) – uses ATP but also produces net ATP
What is toxic about alcohol metabolism?
The ethanol itself is toxic but acetaldehyde is even more toxic hence it needs to be converted to acetate quickly which is inert
* hangover usually combined with dehydration because hormones that retain water get suppressed and water gets excreted
* liver damage
What determines the toxic effects?
Rate of metabolism and thus detoxification of alcohol determines the toxic effects which ADH and ALDH have polymorphisms that affect the rate that acetaldehyde is generated and metabolized which differ between people.
What are ADH and ALH also important for?
There are multiple isoforms of ADH and ALDH so they are not only used to metabolize ethanol.
* some isoforms oxidze retinol (vit A) which is also an alcohol and convert it to its active form of retinal & retinoic acid important for vision, growth and differentiation.
* With acute alcohol intake there is a competitive effect creating relative deficiency of active vit A form which can be seen in fetus development
What is the MEOS pathway?
microsomal ethanol oxidizing system pathway which occurs in the ER microsomes for excessive amounts of alcohol consumption to prevent blood alcohol concentration from becoming dangerously high
* either acute or chronic
What is the reaction of the MEOS pathway?
Uses NADPH and H+ to break down alcohol in the microsome to acetaldehyde using energy from the ADH pathway and goes back into the cytosol to complete the ADH pathway.
What happens with acute excessive intake of alcohol?
Increases toxicity of drugs metabolized via cytochrome P450 pathway because alcohol crowds out metabolism of other drugs so they are not metabolized properly
* i.e. Alcohol inhibits metabolism of barbiturates (CNS depressant) because it because it takes precedence therefore barbiturates remain at high levels in the body & CNS depression increases
What happens with chronic consumption of alcohol?
- results in net energy depletion because alcohol also displaces energy and nutrients from diet so more weight loss in alcoholism
- MEOS pathway gets upregulated because it becomes a power house and adapts to become more efficient at metabolizing alcohol
What is the result of an upregulated MEOS pathway?
- responsbile for alcohol tolerance
- Cross-tolerance to other drugs
- Contributes to vit A deficiency
How is toxicity measured?
blood alcohol concentration (BAC) which is dependant on rate of metabolism.
What are the legal implications of BAC?
administrative sanctions for drivers with BAC of 0.05% to 0.079% (50 to 79 mg of alcohol per 100 ml of blood); legal limit is 0.08%
What effects the rate of alcohol metabolism?
- rate of ingestion
- food intake
- weight (i.e. lean tissue mass / body fluid volume)
- biological sex
- medications genetics (i.e. ADH and ALDH polymorphisms)
What effects the absolute rate of alcohol metabolism between individuals?
Variabilityinabsoluterateofmetabolismbetweenindividualsisdue to variable activity of ADH & ALDH
* Different ethnicities have different isoforms of ADH, resulting in different rates of detoxification of acetaldehyde
* Women have decreased ADH in gastric and liver cells
What are some responses to aocohol consumption?
Is moderate alcohol intake good or bad?
Controversial but toxic effects are mostly dose dependent so likely any amount greater than recommended detrimental, or any amount at all for those with specific polymorphisms. regular moderate consumption associated with:
* Prevention of T2D (insulin sensitivity)
* prevention of dementia
* improvements in heart and circulatory system (HDL, clotting factors, inflammation/ox stress)
* U-shaped relationship for CVD risk and alcohol intake
* benefits in middle-aged adults > young adults
What is reccomended alcohol intake for men and women?
- <1 drink/day women
- <2 drinks/day men
Alcohol associatred organ damage
short term risks of alcohol consumption
- Injuries (esp motor vehicle crashes)
- violence
- alcohol poisoning
- risky sexual behaviors
- miscarriage
- stillbirth
- FASD
long term risks of alcohol consumption
- High blood pressure
- heart disease
- stroke
- liver disease
- digestive problems
- cancer (breast, mouth, throat, esophagus, voice box, liver, colon, and rectum)
- weakening of the immune system
- learning and memory problems (dementia, poor school performance)
- mental health problems (depression, anxiety)
- social problems (family & job-related problems)
- alcohol use disorders & dependence
Effect of increased alcohol consumption on diet
Detrimental effects of alcohol intake >25% of energy affects metabolism, but diet also usually modified
Effects of alcohol consumption on glucose metabolism
increased mito ratios of Acetyl-CoA/CoA and NADH/NAD+
* lactic acidosis from inhibition of PDH and pyruvate to lactate instead
* acute hyperglycemia and hypoglycemia because glycolysis and gluconeogenesis both get inhibited
See slide 21
Effects of alcohol consumption on fat metabolism
increased mito ratios of Acetyl-CoA/CoA and NADH/NAD+ lead to weight gain, fatty liver, hyperlipidemia, ketoacidosis
* pathways diverted to FA and TG synthesis
* increased expression of hepatic lipogenic genes (SREBP1C)
* increased build-up of citrate and feed forward effect on ACC
* increased ketone body formation
How much alcohol activates the hepatic lipogenic pathway?
24gof ethanol/d can lead to DNL in hepatocytes
* a standard drink in Canada has 13.5 g alcohol
What are the categories of fatty liver disease?
- Alcohol-related fatty liver disease (ALD): excessive alcohol intake
- Non-alcoholic fatty liver disease (NAFLD): excessive calorie intake leading to abnormal fat accumulation in the liver (simple steatosis)
What is heaptic steatosis?
intrahepatic fat of at least 5% of liver weight
* Occurs in both ALD & NAFLD From defects in fatty acid synthesis, oxidation & transport, mitochondrial damage due to alcohol and insulin resistance respectively
Common pathophysiology of fatty liver disease
- Simple steatosis
- Hepatitis
- Cirrhosis and Hepatocellular carcinoma
therapies for fatty liver disease
No targeted therapies available
* ALD: abstinence, nutritional support and
* corticosteroids
* NAFLD: weight loss and co-morbidity management
