Skildum: Liver Biochemistry 1 Flashcards
Describe the organization of the liver.
Blood enters the liver through the hepatic a. and portal v (gut)., enters the sinusoids where it interfaces w/ the hepatocytes and exits to the central hepatic vein. (central to peripheral)
Hepatocytes form bile, which enters the bile caniculis and exits through the bile ducts. (peripheral to central)
What is the function of the hepatic stellate cell?
Storage sites of lipids, especially esterified vitamin
What happens when stellate cells are activated?
Lose vit A stores> maintain vit A stores and deposit collagen in the space of disse in response to oxid. stress
What are the hepatic pit cells?
Liver associated lymphocytes
NK cells that protect against VIRUSES and tumor cells
What are hepatic endotheiial cells?
Leaky cells that are perforated by fenestrae and have no basement membrane
What are Kupffer cells?
endocytic phagocytic mphages of the liver that protect the body from BACTERIA
*also mediate liver damage in response to oxidative stress or alcoholism
What is the source of inflammatory mediators that contribute to liver injury?
Kupffer cells
How do substances enter the liver and leave the liver?
Enter: through the blood Leave: through the blood or bile duct
One of the main functions of the liver is to receive and process nutrients. What does the liver do w/ excess protein and carbohydrates?
Converts Protein and carbs>
blood proteins–> cells (serum albumin)
cell glucose–> glycogen (liver)
TG–> VLDL
What are characteristics of the liver that allow it to act as a biochemical sieve to neutralize toxins?
Liver is the FIRST place that ingested things go and acts as a BIOCHEMICAL SIEVE to neutralize toxins.
- low PRESSURE
- high surface area
What is the pathway in the liver to detoxify xenobiotics and metabolites essentially making them more SOLUBLE?
RH> Phase I Reactions> R-OH> Phase II Reactions> Secondary metabolite suitable for excretion
What happens in phase I reactions (cytp450)?
Adds OH groups to substrates (makes metabolites more soluble> excrete primary metabolites)
What happens in phase II reactions?
add to the hydroxyl group: sulfate methyl groups glutathione glucoronate
further increases solubility
*activation can also occur in phase I and phase II
What is an important phase I metabolizing enzyme? What are characteristics of this enzyme?
Cytochrome P450
57 genes; 9 families
all use NADPH; all use O2
overlapping substrate specificity (may act on more than 1 toxin)
expression induced by their substrates (ingesting 1 toxin can increase the capacity to neutralize other drugs)
R+ O2 + (NADPH+ Fe-heme)> ROH, H20
CYP3A4 is an enzyme that metabolizes many drugs, including statins. If two CYP3A4 substrates are ingested how are they metabolized?
The one w/ the HIGHER affinity will be metabolized faster
What juice contains an inhibitor of Cyp 3A4?
Grapefruit> will increase conc of drugs that are metabolized by that enzyme
What drugs are metabolized by CYP3A4?
lovastatin (greatest affinity>fastest)–> conc of other drugs will increase
Simvastatin
atorvastatin
How does vinyl chloride (input for plastic) damage the liver?
CYP2E1 (phase I reactant) coverts it to a reactive EPOXIDE>
DNA cell damage>
Acute toxicity/death to liver cells>
chronic exposure>
ANGIOSARCOMA (malignant neoplasm of endothelial cells)
Phase II>
glutathione S transferase makes it excretable through bile
What is the MC cause of acute liver failiure?
Acetaminophen
What are sxs of early acetaminophen toxicity?
Nausea
vomiting shortly after ingestion
What are sxs of acetaminophen toxicity 24-48 hrs after ingestion?
Aminotransferase levels increase
Lactate dehydrogenase increases
Prothrombin time increases
What are sxs of acetaminophen toxicity 72-96 hrs after ingestion?
Jaundice Hepatomegaly Bilirubin increases (indicates acute kidney injury) Encepholopathy / Coma Hypotension Hypoglycemia; metobolic acidosis Death by general organ failure
What predicts the severity of acetaminophen poisoning?
Serum CONCENTRATION of acetaminophen
What are xenobiotics normally excreted?
Xenobiotic–>Transferase> conjugated xenobiotic> urinary excretion
Xenobiotic> CYP450> oxidized xenobiotic> different transferase> conjugated oxidized xenobiotic> urinary excretion
What is the pathway for acetaminophen induced liver toxicity?
The oxidized xenobiotic (formed by CYP450) is not converted and excreted, but instead lingers and causes toxicity.
What is a common cause of liver failure?
Acetaminophen poisoning
How does Acetaminophen poisoning cause liver failure?
Cyp2E1 converts acetaminophen to NAPQI.
*sulfotransferase uses PAPs
NAPQI can create adducts on cell proteins and kill cells. (ethanol induces cyp2E1 expression and increase the rate of NAPQI production> BAD)
What is cimetidine?
A drug that blocks CYP2E1 thereby preventing acetaminophen poisoning…maybe
- Also blocks H2 receptors
- N acetyl cysteine increases GSH and redudes NAPQI
What depletes hepatic GSH?
Ethanol metabolism
What forms GSH?
glutamic acid
cysteine
glycine
What is MEOS?
microsomal ethanol oxidizing system
Converts Ethanol> acetaldehyde
-needs reducing power of NADPH
What enzyme uses ethanol as a substrate?
Cyp2E1
What is responsible for the long term damage to the liver associated w/ ethanol consumption?
Acetaldehyde produced by ADH and Cyp2E1
How does acetaldehyde lead to fibrosis in the liver?
Acetaldehyde> actives kupffer cells> secrete TGF-B and ROS> Stimulates stellate cell> secretion of collagen and metallo proteases> FIBROSIS
*more this happens you move from fibrotic disease (reversible) to cirrhosis
How does the liver regulate blood glucose in the fed state (oxidation)?
Insulin>
conversion of excess carbs (glucose) to storage forms>
triglyceride synthesis
glycogen syntehsis
How does the liver regulate blood glucose in the fasted state?
Glucagon/Epi>
Liver converts stored glycogen/AA>
Glucose
- glycogen degradation
- gluconeogenesis
What does glycogen storage disease cause?
fasting hypoglycemia
What is the pathway that turns glycogen into blood glucose?
Glucagon/Epi> Glycogen> glu-1-p> glu-6-p> (< glyconeogenesis) glucose> transfered to blood
What enzyme interconverts glu-1-p and glu-6-p?
PGM1 (phosphoglucomutase)
What is cholesterol synthesized in the liver used for?
Bile salts- essential for uptake of fat, taken up through ileum, recycled in liver (bile salts that aren’t taken up are the major way we lose cholesterol in the body)
Cell membranes
Store FA
Steroid hormones
What happens to excess carbohydrates in the liver?
Carbs> FA> TG> VLDL> LPL> IDL> HTGL> LDL
*LDL particles can be recycled by the liver
What happens to excess N formed by AA catabolism?
Must be converted to urea for excretion
urea cycle
Where do the N that form urea come from?
Free ammonia
Aspartate
What form does excess N take as it is transported from peripheral tissues to the liver?
Amino acid GLUTAMINE (blood N buffer)> released into blood>
enters liver>
converted to NH4 by Glutaminase and GDH
How is the breakdown of skeletal muscle protein processed?
Breakdown of skeletal muscle protein> Gln> blood from gut> liver> Glutaminase> carabomyl phosphatase synthetase 1 (CPS1) blood to the heart
Where is glutaminase and CPS1 expression the highest?
periportal hepatocytes
Where is glutamine synthase restricted to?
perivenal hepatocytes
What cells in the liver secrete Wnt? Where is Wnt concetration the highest?
Central vein endotheilal cells secrete Wnt>
Wnt concentration is HIGHEST closest to the central vein
Where are GS negative cells located?
Closest to the portal triad
Where are GS positive cells located?
Closest to the central vein
What is the importance of different expression of Wnt in processing N?
Creates a ‘safe zone’ for free ammonia to be a substrate for the urea cycle, without free ammonia being released into the general circulation.
Maintaining blood glucose while fasting is dependent on…
the urea cycle
Acetaminophen solubility can be increased by glucoridination and sulfation independent of cytp450 enzymes. What provides the sulfur for the sulfotransferases.
Sulfotransferases use PAPs as a sulfur donor.
Sulfotransferases are used to metabolize acetaminophen
Mphages that mediate inflammation in the liver are called…
Kupffer cells
What event occurs AFTER Wnt binds its receptor?
B catenin translocates to the nucleus
