3 tox response of liver Flashcards
why are certain organs “targets” of xenobiotics?
-toxicokinetic and toxicodynamic factors
what is the main question of this lecture?
why is the liver susceptible to toxicity arising from xenobiotic exposure?
-the liver as a target organ
what are the components of the liver (liver anatomy)?
-parenchymal=hepatocyte (primary liver cells)
what is the graph of liver anatomy?
what are Kupffer cells?
-the liver has resident macrophages (Kupffer cells) that release pro-inflammatory mediators that can be involved in oxidative stress (release amounts of ROS to kill bacteria, “zaps”)
what does biliary excretion involve?
-biliary excretion involves active transport “pumps” that can up-concentrate toxic metabolites by 5000-fold in canaliculi (green)
what are the toxic responses of the liver?
- steatosis
- necrosis
- cholestasis
- cirrhosis
- carcinogenesis
what is steatosis?
“fatty liver”
-when >5% lipid within cells
-can be due to both acute or chronic exposures
-reversible effect
-e.g. ethanol (binge drinking and chronic drinking)
-clinical marker: serum triglycerides (when high=more drinking)
what is necrosis?
-focal (central, midzone, peripheral) or massive (throughout liver)
-usually acute exposure; irreversible
-usually involves decreased ATP and/or altered Ca2+ regulation
-e.g. acetaminophen, carbon tetrachloride (CCl4) can cause massive hepatocellular necrosis
what are the clinical markers of necrosis in the liver?
clinical markers: alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) in blood plasma/serum
-ALT, AST, and GGT are abundant in liver cells and are released into bloodstream when cells die via necrosis
-ALT, AST, and GGT are also used as clinical markers of toxicity in other organs (e.g. kidney, heart)
what does the graph of massive necrosis look like?
darker stains=mass necrosis areas
what is cholestasis?
-“canalicular cholestasis”: decreased bile formation and biliary secretion
-symptoms: yellowish tinge in skin and eyes due to bilirubin (normal breakdown product of heme catabolism)
-e.g. ethanol, certain metals, steroids, and certain drugs
-clinical markers: alkaline phosphatase (ALP), GGT and bilirubin (concentration) in plasma
what is cirrhosis?
-extensive fibrosis throughout liver (“scarring”)
-e.g. chronic ethanol consumption
-other forms of liver injury involved in mechanism:
ethanol->oxidative stress-> mitochondrial damage-> steatosis, necrosis-> fibrosis
-clinical markers: plasma, ALT, AST, GGT
what is carcinogenesis of the liver?
-very common form of cancer
-hepatocellular carcinoma is most common
-clinical (blood) marker: alpha-fetoprotein (AFP) is elevated in liver but also other factors
-biopsy, MRI, CT scans for diagnosis
what is the summary of the toxic responses of the liver? what do they have in common?
steatosis, necrosis, cholestasis, cirrhosis, and neoplasia have in common:
-easily produced in laboratory animals
-many xenobiotics can cause several or all of these toxic effects
comprehensive question: why is the liver a target organ, give me six reasons?
-increased expression of CYP enzymes (have most expression, compared to other organs with few expressions)
-enzymes in liver have highest amount and expression
-first place a xenobiotic (first line of defense) hits besides the GI tract
-enterohepatic cycling
-preferential distribution: there is a very large amount of perfusion in the liver (massive bloodflow)
-preferential distribution: liver also has certain binding proteins that can be high affinities for certain xenobiotics
-specialized macrophages that can be involved in immune responses and oxidative stress bursts
what is the biological basis for the hepatotropic toxicity of xenobiotics?
what is APAP?
acetaminophen (APAP) as a liver toxicant
-CYP2E1=if greater activity, you produce great amounts of toxic metabolite (involved in bioactivation into toxic metabolite)
how can we experimentally investigate complex toxic mechanisms?
“knockout” models are powerful experimental tools in mechanistic toxicology
what gets knocked out?
what are the learning points of this lecture of liver as a target organ?
-there are numerous toxicokinetic and toxicodynamic explanations as to why the liver is susceptible to xenobiotics
-for any target organ such as liver, anatomy and physiology (“form and function”) are important considerations
-steatosis, necrosis, cholestasis, cirrhosis, and neoplasia are the most common hepatotoxic effects
