hepatotoxicity

Question 1

overview the function of the liver

Answer 1

-principle organ involved in urea and glycogen synthesis.
- synthesizes bile acids which are secreted through organic anion transporters
- synthesis of albumin, clotting factors, triglycerides, bilirubin, haem and recycling of iron
-surveillance role alongside immune system (bacterial lipopolysaccharides can end up in the liver. )

detoxifying metabolism:
-oxidative and reductive metabolism
- conjugating metabolites with glucuronic acid sulphate or glutathione.

Question 2

what are the liver cell types and their functions

Answer 2

hepatocytes: metabolising enzymes found here to metabolise drugs

bile duct epithelia

endothelial cells: blood vessels

kupffer cells: liver macrophages

stellate/ito cells: fat/vit a storing cells

also: oxygen tension gradient between hepatic portal area and central vein area. cyp enzymes most prominent here. toxins also more prominent as main area of metabolism.

Question 3

how do liver function biomarkers indicate whether functions are sub-optimal/failing

Answer 3

raised blood ammonia: observed with liver failure due to cirrhosis

alanine aminotransferase in blood: damage to hepatocytes

aspartate aminotransferase in blood: damage to hepatocytes (but can be released from other damaged organs)

alkaline phosphatase: damage to bile duct (also released from kidneys and bones)

gamma glutamyl transpeptidase: suggests bile duct damage but also associated with renal damage

blood bile salts (bilirubin/biliverdin) or blood bile acids like cholic acids can indicate cholestasis (blockade of bile ducts/biliary secretion)

micro rna (non-coding RNA that repress gene expression) mir-122 is a sensitive liver specific marker of hepatic injury in blood samples

Question 4

what are some examples of reactive metabolite formation leading to liver necrosis

Answer 4

ex:
paracetamol
menadione
cyclophosphamide
mechanism: the carbonyl groups in these drugs reactive metabolites react with glutathione leading to its depletion.
some formulations include antidote n-acetyl cysteine.

ex:
carbon tetrachloride

ex:
methapyrilene
antihistaminergic and anticholinergic medicine that was used to treat insomnia
was carcinogenic in rats with chronic treatment
forms reactive metabolite which depletes glutathione stores. also some evidence of mitochondrial toxicity and reduced fatty acid oxidation (steatosis) and elevated ammonia.
when glutathione used up the active metabolite leads to non-genotoxic cancers via histone methylation

Question 5

what are some cyp450 inducers and what effects could they have

Answer 5

inducing liver enzymes can lead to enhanced hepatotoxicity and increased clearance of co-administered drugs
ex: corticosteroids, phenytoin, barbiturates, aromatic hydrocarbons, ethanol

Question 6

what are some cyp450 inhibitors and what effects could they have

Answer 6

may lead to toxicity in remote organs due to kinetics of co-administered drugs being altered
ex: cimetidine, erythromycin, isoniazid
grapefruit juice, inhibits 3a4 to increase half life of ca2+ channel blockers like nifedipine leading to an increased drop in BP.

Question 7

how can toxicants cause liver toxicity via cholestasis

Answer 7

chlorpromazine

tetracycline

erythromycin

tamoxifen

thioacetamide
oxidized to very reactive thioacetamide s,s- dioxide
which reacts with amino groups esp lysine residues and phosphatidylethanolamine. unrealted to glutathione. causes cholestasis and is a non-genotoxic carcinogen

Question 8

how can toxicants cause liver toxicity via steatosis

Answer 8

amiodarone

carbon tetrachloride

tamoxifen

ethanol

Question 9

how can toxicants cause liver toxicity via cancer

Answer 9

nitrosamines (n-nitrosodimethylamine)
can be generated from ranitidine decomposition
also found in food treated with nitrite and cigarettes.
activated by cyp2e1 (which can be induced by alcohol) to ethanolamine forming dna adducts (covalent modifications)
they methylate dna and are genotoxic carcinogens

aflatoxins

pyrrolizidine alkaloids

methapyrilene
non-genotoxic carcinogen. active metabolite modifies histone methylation.

Question 10

how can toxicants cause liver toxicity via vascular damage

Answer 10

amnitin

pyrrollizidine alkaloids

Question 11

give examples of altered liver metabolism leading to toxicity in remote organs or the liver via changes in kinetics of other drugs

Answer 11

pimozide is linked to sudden death due to qt prolongation. an extended half life due to enzyme inhibition enhances the risk of qt prolongation.