Liver toxicity Flashcards
Liver characteristics that make it susceptible to toxicity
it is in contact with a wide range of drugs and is the main organ for biotransformation, thus leading to the accumulation of metabolites
ethanol metabolism in chronic consumption
involves CYP2E1, oxygen and NADPH
normal ethanol metabolism
Alcohol dehydrogenase in the presence of NAD breaks it down to acetaldehyde.
acetaldehyde dehydrogenase further breaks down the molecule to acetate and is used in the Krebs cycle.
acute alcohol liver toxicity symptoms
depressed CNS
chronic alcohol liver toxicity symptoms
steatosis -> cirrhosis -> liver cancer
5 mechanism of liver toxicity by alcohol
- affects membrane fluidity and modifies membrane proteins
- forms free radicals and reactive oxygen species when metabolised by CYP2E1
- form phosphatidylethanol and dihydroxyacetone phosphate which forms glycerol and accumulates in the liver
- produces fatty acid ethyl esters that impairs organelle function
- increased NADH:NAD ratio which impairs mitochondria ability to oxidise fatty acid
NSAID mechanism
inhibit COX which inhibits prostalglandin production
acetaminophen mechanism
metabolised by CYP450 to NAPQI which is a reactive intermediate
acute aflatoxin symptoms
abdominal pain, emesis, steatosis
chronic aflatoxin symptoms
liver carcinoma by B1
aflatoxin mechanism
metabolised by CYP450 to reactive intermediate AFBI epoxide
- binds to DNA causing mutagenesis
- further metabolised to dialdehyde then binds to proteins
4 proposed idiosyncratic drug induced liver injury (IDILI) mechanism
- multiple determinant
- fail to adapt (drug interferes with cell adaptation)
- inflammatory stress (activates immune cells that release cytokines)
- adaptive immunity (after the formation of reactive metabolites)
halothane mechanism
CYP450 metabolises to reactive metabolite trifluoroacetyl chloride which binds to proteins. these proteins are transported to the cell surface and recognised by APC, inducing an immune response.
