Metabolic Functions Of The Liver Flashcards
Why does the liver regulate carbohydrate metabolism?
To maintain blood glucose
Why does the liver regulate fat metabolism?
Synthesis and beta oxidation
Why does the liver regulate protein metabolism?
Plasma protein synthesis
Detoxification of ammonia (urea formation)
What specialised molecule does the liver synthesise?
Bile acids
Haemin
What else does the GI tract supply to the liver?
Major dietary nutrients (proteins and carbs- not lipids)
Where does the livers blood empty into and why?
Inferior vena cava
Ensures fast circulation of products
Where does the bile duct empty into?
The gut
What are the routes of ethanol metabolism (and their % prevalence)?
Oxidation through activity of alcohol dehydrogenase (90%)
Miscrosomal oxidation using cytochrome P450 (10-20%)
How much alcohol does the body metabolise through oxidation per hour?
10g
What does methanol oxidise to?
Formaldehyde
Why is the oxidation of methanol bad?
Formaldehyde is super toxic and can lead to blindness, paralysis and loss of consciousness
What isoform(s) of ALDH do Caucasians have?
ALDH-1 and 2
Where is ALDH2 found?
Mitochondria
What percentage of certain ethnic groups only express which enzyme?
40%
ALDH1
What are the symptoms of ethanol intolerance?
Vasodilation, facial flush, tachycardia and nausea
What happens in the microsomal ethanol-oxidising system?
Ethanol is oxidised by members of cytochrome P450 family
What does the microsomal ethanol-oxidising system generate?
Acetaldehyde
What does the microsomal ethanol-oxidising system consume?
NADPH
What is NADPH needed for?
Synthesis of gluthathione (antioxidant) -> increased oxidative stress
When does acetaldehyde accumulate?
Excessive ethanol intake
What are the effects of acetaldehyde?
- Inhibited enzyme function
- Decreased secretion of serum protein and VLDL in the liver
- enhanced free radical production
What do free radicals do in the body?
Lead to tissue damage (inflammation and necrosis)
How many stages of liver damage are there?
3
What happens in the first stage of liver damage?
Fatty liver
What happens in the second stage of liver damage?
Alcoholic hepatitis, groups of cells die -> inflammation
What happens in the third stage of liver damage?
Cirrhosis (fibrosis, scarring and cell death)
What happens when your liver is cirrhotic?
Liver cant function so
Ammonia accumulates -> neurotoxicity, coma and death
What % of alcoholics get cirrhosis?
25
What % of cirrhosis is due to alcohol?
75
What are the consequences of having high NADH levels as a result of high ethanol metabolism?
- inhibits glucogenesis and stimulates the conversion of pyruvate -> lactate
- inhibits fatty acid oxidation
- Inhibits TCA cycle and acetyl coA increases inhibition further
- stimulates fatty acid synthesis
- stimulates formation of TGs
What does the increase in lactate lead to?
Hypoglycaemia and lactic acidosis
What molecules inhibit glucose metabolism and how?
Acetyl CoA, NADH and ATP
Inhibiting PFK and pyruvate dehydrogenase
What are xenobiotics?
Compounds with no nutritional value
Give some examples of xenobiotics
Plant metabolites Synthetic compounds Food additives Agrochemicals Cosmetics Drugs
What organ plays a big role in xenobiotics metabolism?
Liver
What is the aim of xenobiotic metabolism?
Make them harmless and more readily disposed of
What are the three common phases in the metabolism of xenobiotics?
Phase 1 (oxidation) Phase 2 (conjugation) Phase 3 (elimination)
What happens in phase 1 of xenobiotic metabolism?
Oxidation mainly, but also hydroxylation and reduction
What does the modification do in phase 1 xenobiotic metabolism?
Increases solubility and introduces functional groups which enables participation in further reactions
What is phase 1 xenobiotic metabolism promoted by?
Cytochrome P450
Where is cytochrome P450 mainly found?
Liver and intestinal cells
How many enzymes are in the cytochrome P450 family?
50 enzymes
What do the cytochrome P450 enzyme family all have in common?
All haem proteins that relate to mitochondria enzymes
Where are the cytochrome P450 enzymes found within a cell?
Endoplasmic reticulum
What induces cytochrome P450 enzymes?
Their own substrates or related substrates
What groups are added in phase 2 xenobiotic metabolism?
Glutathione
Glucaronic acid
Sulfate
Why are the groups added in phase 2 xenobiotic metabolism?
Increase solubility and target for excretion
Why is the liver important in drug metabolism?
- xenobiotic metabolism is part of body’s natural defence
- metabolism of drugs plays a significant role in their effectiveness
What does metabolism of drugs do to their effectiveness?
Either increase or reduce depending on the drug
Can the body distinguish between harmful compounds and beneficial compounds?
No
What is aflatoxin B1 (Subscript 1) produced by?
Aspergillus flavus fungus
What happens when aflatoxin B1 undergoes metabolism?
Activated by P450 isenzymes -> epoxied formation and hepato-carcinogenesis
What do statins do?
Inhibit HMG-CoA
What are statins degraded by?
CVP3A4
What is CYP3A4 actively inhibited by?
Grapefruit juice
What happens after the compounds have been modified?
- Small, water soluble molecules (<60000 kDa) can be removed by the kidney
- actively transported into bile and then into intestines
