Liver Metabolism 7: Detoxification And Alcohol Metabolism Flashcards
Review of how many kcal/g is found in the 3 main macronutrients and alcohol?
Carbohydrates = 4 kcal/g
Protein = 4 kcal/g
Fat = 9 kcal/g
Alcohol = 7 kcal/g
How does the liver break down ethanol?
Goes through one of two pathways
1) alcohol dehydrogenase (80-90%)
2) Microsomal Ethanol-Oxidizing System (MEOS) pathway (10-20%)
- *both pathways produce acetaldehyde-> acetate**
- acetate is either sent to muscles for fuel or converted into acetyl CoA and then either
1) ketone bodies in the liver
2) Palmitate cholesterol
How does the MEOS system work?
only metabolizes up to 20% of a moderate drink and has a high Km for ethanol (requires quite alot to be saturated)
Is induced at transcriptional posttranscriptional and posttranslational level in heavy drinkers
- ** induction potentiates toxicity of acetaminophen
Takes ethanol in the ER and converts it to acetaldehyde in the cytosol
What CYP protein has the highest affinity for ethanol?
CYP2E1
What is the primary enzyme and rate limiting step of ethanol metabolism?
Alcohol dehydrogenase (ADH) - *requires NAD+ to be available since this is the limiting factor*
Two types:
- ALDH2 = mitochondrial type
- ALDH1 = cytosolic type
Metabolizes 80-90% of the ethanol in liver cells
Lower Km than MEOS system (so saturates really fast)
- *ethanol metabolism follows zero-order kinetics**
- most people metabolize 10g of alcohol per hour
What is the physiological effects of acetaldehyde?
It’s a very toxic component that in excess accounts for most of the physician damage in chronic alcoholics
Symptoms:
- flushing
- nausea/vomiting
- “being drunk” symptoms
Aldehyde dehydrogenase (ALDH)
Two subtypes:
- mitochondrial ALDH2
- cytosolic ALDH1
some eastern Asian populations have polymorphism in ALDH2 genes (30-40%) which results in a dominant negative phenotype. This results in “oriental flush” in response to drinking alcohol (vasodilation/facial flushing and tachycardia)
The purpose of this enzyme is to provide natural “protection” from alcoholism
ALDH inhibition = Disulfiram (Antabuse)
What are the metabolic effects of alcohol abuse?
Hypoglycemia (in fasted state)
Transient hyperglycemia (in fed state)
Lactic acidosis
Hyperuricemia
Ketoacidosis
Hyperlipidemia and fatty liver disease
What is the proposed model behind liver fibrosis in chronic alcoholics?
Acetaldehyde is consumed in excess by kupffer cells in liver tissue which produces activated kupffer cells
Activated kupffer cells release TGF-B and respiratory bursts/ROS which casues stellate cells to be activated in response
Activated stellate cells produce MMPs and extracellular matrix collagen = fibrosis
What two vitamin deficiencies are most common among alcoholics?
Folate = megaloblastic anemia
Thiamine = wernicke-korsakoff syndrome
Why is drinking during pregnancy so dangerous?
High levels of estrogen seen in pregnancy inhibits Alcohol dehydrogenase enzymes (ADH)
This causes mass ethanol to remain in the blood which cross the placenta easily
- fetus has NO ADH, so metabolism occurs = toxic and fetal alcohol spectrum disorder
What are the heath benefits from moderate-mild alcohol drinking
Helps limit the following:
- coronary heart disease
- gallstones
- strokes
- diabetes
- osteoporosis
- *however increases risks of**
- cancers
- injury/fibrosis
- hemorrhagic stroke
How to treat both methanol and ethylene glycol poisoning
IV fomepizole = competitive inhibitor of ADH
can also give ethanol for both since it also competitively binds to ADH
*** the reason both of these work is methanol and ethylene glycol ARE NOT toxic until they are metabolized. If not metabolized, will be eliminated from the body
What are the effects of DEAK vitamin deficiencies and toxicity
Vitamin A:
- deficiency = night blindness and xerophthalmia (dryness of eye which causes keratin synthesis and blindness eventually)
- toxicity = dry skin, liver cirrhosis, fragile bones, teratogenic in pregnant women
Vitamin D:
- deficiency = osterodystrophy and osteomalacia/rickets
- toxicity = hypercalcemia and kidney stones
Vitamin K:
- deficency = casues unusual bacterial growth and spontaneous bleeding
- toxicity = NOT POSSIBLE
What does Km and Vmax stand for?
Km = affinity for substrate
- high Km = low affinity for substrate
- low kM = high affinity for substrate
Vmax = how fast an enzyme metabolizes it’s substrates
- high Vmax = works fast and metabolizes fast
