GUT- Metabolic Functions of The Liver Flashcards
what are the two pathways responsible for the elimination of ethanol
oxidation through the activity of alcohol dehydrogenase - 90%ish
microsomal oxidation using cytochrome P450- 10-20%
what are the steps involved in the oxidation via alcohol dehydrogenase pathway
ethanol is converted to acetaldehyde by alcohol dehydrogenase
acetaldehyde is then converted to acetate in the mitochondria by aldehyde dehydrogenase
acetate is then converted to acetyl CoA by acetyl CoA synthase
why are some people ethanol intolerant
there are two isoforms of the aldehyde dehydrogenase - 1 and 2
isoform 2 is more functional than one
some ethnic groups only have isoform 1 and can therefore be ethanol intolerant
what are the steps involved in the microsomal oxidation using cytochrome P450 pathway
ethanol is oxidised by members of the CYP450
this pathway generates acetaldehyde
this system consumes NADPH required for the synthesis of antioxidant glutathione - increases oxidative stress
what is the issue with acetaldehyde
highly reactive and can accumulate with excessive ethanol intake
can inhibit enzyme function
in the liver this can lead to a reduction in the secretion of both serum protein and VLDL
it can also enhance free radical production - leads to tissue damage such as inflammation and necrosis
how many stages of alcohol liver damage are there
3
what are the three stages of alcohol liver damage
stage 1- fatty liver
stage 2- alcoholic hepatitis - groups of cells die resulting in inflammation
stage 3- cirrhosis which induces fibrosis scarring and cell death
why does a cirrhotic liver lead to cell death
as the liver cannot function properly, ammonia will accumulate resulting in neurotoxicity, coma and death
what are the consequences of high ethanol metabolism
high NADH inhibits gluconeogenesis and stimulates the conversion of pyruvate to lactate leading to hypoglycaemia and lactic acidosis
high NADH inhibits fatty acid oxidation and stimulates fatty acid synthesis and the formation of triglycerides
acetyl-CoA, NADH and ATP inhibits glucose metabolism by inhibiting PFK and pyruvate dehydrogenase
NADH inhibits the TCA cycle and acetyl CoA increases inhibition further
acetyl coA results in ketone body formation and the stimulation of fatty acid synthesis
define xenobiotic
compounds with no nutritional value such as
plant metabolites
synthetic compounds
cosmetics
drugs
how does the liver metabolise xenobiotics
phase 1- oxidation - modification increases solubility and introduces functional groups which allow for participation in other reactions - promoted by CYP450
phase 2- conjugation - modified by the addition of glutathione, glucuronic acid and sulphate - this increases their solubility and targets them for excretion
phase 3- elimination - after metabolism small water soluble molecules can be excreted by the kidneys - they can also be actively transported into the bile and then into the intestine
why are the CYP450 enzymes important?
they are inducible by both their own substrates and related substrates - important in the metabolism of drugs
why is it important to understand how the liver metabolises drugs
metabolism of drugs is part of a natural defence but it cannot distinguish between harmful and therapeutic substances
this is important to understand to understand the effectiveness of drugs when given in a therapeutic manner
outline the metabolism of paracetamol under normal conditions
acetaminophen (paracetamol) is mostly metabolised by UDP-glucuronyl transferase or sulpho-transferase and is excreted by the kidneys
a small amount is metabolised by CYPE21 to form NAPQI which is toxic
NAPQI can be converted to mercapturic acid by glutathione s-transferase - it can also act with proteins to for NAPQI-protein adduct which leads to tissue damage and cell death
combining paracetamol with ethanol has two effects on the metabolism of paracetamol in the liver- what are they
ethanol inhinits NADPH which inhibits Glutathione - which reduces NAPQI being converted into meracupturic acid
ethanol also stimulates CYP2E1 to form NAPQI- increasing levels of NAPQI which increases protein binding and tissue damage
