3 tox response of liver

Question 1

why are certain organs “targets” of xenobiotics?

Answer 1

-toxicokinetic and toxicodynamic factors

Question 2

what is the main question of this lecture?

Answer 2

why is the liver susceptible to toxicity arising from xenobiotic exposure?
-the liver as a target organ

Question 3

what are the components of the liver (liver anatomy)?

Answer 3

-parenchymal=hepatocyte (primary liver cells)

Question 4

what is the graph of liver anatomy?

Answer 4

Question 5

what are Kupffer cells?

Answer 5

-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”)

Question 6

what does biliary excretion involve?

Answer 6

-biliary excretion involves active transport “pumps” that can up-concentrate toxic metabolites by 5000-fold canaliculi (green)

Question 7

what are the toxic responses of the liver?

Answer 7

1. steatosis
2. necrosis
3. cholestasis
4. cirrhosis
5. carcinogenesis

Question 8

what is steatosis?

Answer 8

“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)

Question 9

what is necrosis?

Answer 9

-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

Question 10

what are the clinical markers of necrosis in the liver?

Answer 10

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)

Question 11

what does the graph of massive necrosis look like?

Answer 11

darker stains=mass necrosis areas

Question 12

what is cholestasis?

Answer 12

-“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

Question 13

what is cirrhosis?

Answer 13

-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

Question 14

what is carcinogenesis of the liver?

Answer 14

-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

Question 15

what is the summary of the toxic responses of the liver? what do they have in common?

Answer 15

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

Question 16

comprehensive question: why is the liver a target organ, give me six reasons?

Answer 16

-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

Question 17

what is the biological basis for the hepatotropic toxicity of xenobiotics?

Answer 17

Question 18

what is APAP?

Answer 18

acetaminophen (APAP) as a liver toxicant
-CYP2E1=if greater activity, you produce great amounts of toxic metabolite (involved in bioactivation into toxic metabolite)

Question 19

how can we experimentally investigate complex toxic mechanisms?

Answer 19

“knockout” models are powerful experimental tools in mechanistic toxicology

Question 20

what gets knocked out?

Answer 20

Question 21

what are the learning points of this lecture of liver as a target organ?

Answer 21

-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