What aa supplies the liver
hepatic aa
What is the portal triad of the liver
hepatic aa
bile duct
portal vein
What is the flow of blood thru functional units of liver
portal triad-> sinusoids-> central vein
What is the site of biotransformation in the liver and what is the function it
hypatocyte is site of major biotrasformation
-Creates molecules more water soluble so it can be excreted by kidney
What are the 3 zones blood must move thru to get to the central vein
- Periportal
- Midzonal
- Centrilobular
How does drug move thru hepatocyte
hepatocyte allows free drug to move thru endothelial wall into the sinusoids
-some of parent drug will go thru biotransformation and some will get thru without be be biotransformed on subsequent passes
How does bile flow thru the functional units of the liver
hypatocyte-> bile ductules-> portal triad
What are the following phases drugs that enter our system can go thru (4)
- Phase 1 -> excreted
- Phase 1->2->exreted
- Phase2->excreted
- Phase 2->1->excreted
What is the general steps and goal of phase 1 rxn
P450 enzyme system will change parent molecule -> intermediate-> hydroxylated compound
(aliphatic oxidation)
-substance more water soluble
What are the enzymes required for phase 1 rxns (3)
Microsomal mixed function oxidase
Monooxygenase system
P450 system
Requirements for p450 system to work (4)
- Endoplasmic reticulm
- P450
- Flavoprotein-NADPH0 cytochrome p450 recuctase
- Molecular oxygen
What kind of rxn is a phase II rxn and what is it doing different than phase I rxn
Glucuronidation rxn
-Adds to molecules while phase I took things off but also makes things water soluble
Steps of phase II rxn
Generation of glucuronide (UDPGA) from glucose via UDP glucose intermediate
-UDPGA then transferred to molecule undergoing biotransformation
What do you need to transfer UDPGA to molecules
UDP glucuronosyltransferate found in liver, gut, kidney, lung, adrenal gland, spleen etc
How can carbon tetrachloride be biotransformed in phase I rxn
can be biotrandsformed into phosogene, chloroform, lipid peroxidation or binds molecules causing irreversible binding
How can phase 1 rxn be induced to be more toxic
Some indv who chronically take meds/drugs may have induced p450 system resulting in even more free radical formation
What is an example of an inhibitor of CYP isoenzymes (p450) and what do they do
reduces enzyomatic activity impacting half life
Grapefruit juice
What is the main pathway for acetaminophen
Will go thru phase II pathway where UDPGA is added to make glycuronide
If acetaminophen is overwhelming system what happens
Will go thu phase 1 where p450 will act on it and create a carbonium ion (can lead to cellular necrosis)
What can covert carbonium reactive intermediate to non toxic molecule
Glutathione transferase
What is used in ppl with acetaminophen who injested high amounts
N-acytl cystein can be used to promote gluitathione and possible stim biotransformation of intermediate
What is found in zone 1 (periportal) of hepatocyte
more aerobic and have more GSH + alc dehydrogenase
What is found in zone 3 (centrilobilar) of hepatocyte
higher level of chytochrome p450 (why this area is more damaged)
What is a probe drug for CYP2D6
Dextromethorphan
What do kupffer cells do and where are they found
line sinusoids and are involved in the removal of foreign substances from blood by phago
Why is the liver targeted for toxic substances
- able to biotransform many substances but can form free rads in process
- can interfere w endogenous metabolic pathways
- billiary excretion of xenobiotics may lead to high conc of these substances in bile
- blood supply of liver ensures high expose to toxic substances absorbed
- enzyme induction can lead to faster generation of toxins
How is methanol biotransformed
biotransformed into formaldehyde and then to formic acid which causes metabolic acidosis + optic n damage
What is the antiddote to methanol poisoning
fomepizole is a competative inhibutor of alc dehydrogenase
What is steatosis and mc cause
Accululation of triglyeries in hepatocytes
Ethanol mc cause
What is cirrhosis and mc cause
Chronic lesion resulting from repeated injury and subsequent repair
Ethanol Mc cause
What is Cholestasis what substancce indicates damage
Bile stasis or dmage to the bile ducts, ductules or canaliculi
Alkaline phosphatase
What two substances indicate hepatocellular damage
Alanine anino transferase
Aspartate amino transferase
