Two mjor funcations of the liver
1.central for recieivng and recyling - this is allowed particullarly because of gaps between endothelial cells and slow blood flow allowing for exchange between sinosodial and hepatocytes
2. Site for inactivati/ detox
1. Glucose regulation (glycogen, gluconeogensis), Choelsterol syn and elimination, bile syn and elimination. VLDL(TAGs) syn and export, Ketone body syn and export, Ammonia and urea cycle, synthesis of heme and bilirubin elimination, reutilization of purines and pyrimidines, synthese of special molecules.
What are xenobiotics and their general way of elimination>
Kenobiotics are wast metabolites in diet or peropheral circulation that cannot be degraded and eliminate by toerh cells
Gernally Xenobiotics under phase 1 rxns (reduction, hydrolisis, oxidation, hydroxylation) becoming the primary metabolie
If they still can't be excreteed they undergo Phase 2 (conjugation, sulfation, methylation, glucoronidation, acetylation) becoming secondary metabolites and are ready for excretion
What things do phase 1.phase 2 reacions do?
1. Process endogenous (of use) molecules to an active form
2. Process xenobiotics to
A. Activate them
B. Inactivate them
c. turn them into toxins and carcinogens.
What are Cytochrome P450 proteins?
A family of heme proteins, called cytochrome P450, catalyzes the oxidation of a variety of diverse molecules in prokaryotes and all mammalian cells except mature red blood
cells and skeletal muscle cells.
Substrates can be endogenous molecules like steroids/FA (prostagladins, leukotrienes) or drugs, food additives industral by products.
Explain the steps in Phase 1 reactions of cytochrome 450
The heme prtein contains a ferric ion that needs to become ferous (Fe2+) with the use of NADPH
2. Molecular Oxygen binds to the Fe2+ (Ferrous)
3. Use NADPH to reduce the substrate to A-OH (product) and iron becomes ferric again and we make H20
NADPH + H+ + O2 + A-H ----->>> NADP+ + H2O + A-OH
two places that you find cytochrome 450
ER and mitochondria depending on the subfamily and the need
Explain what happens with Cytochrome 450 ain steroid synthesis
CYP450 is rquired to metabolize cholesterold to aldosterone (responsible for salt and water balance) and cortisol( governs carb protein and lipid metaboilism)
The Committed step is Choleterol cleaved by CYP11A into pregnenolone in the adrenal mitochondria using NADPH and O2
Pregnenelone is transfer to the cytosol and oxidized to progesterone which uses 21-hydrolase(remember this) to make mineracorticoid and gluccorticoid pathways and none are made without the CYP enzyme.
Explain oxygenation of prostaglandins, eicosanoids and Vitamin D.
Cytochrome CYP27 family members metabolize vitamin D3 to produce 1,25-dihydroxy vitamin D3 the active from of this hormone.
Cytochrome CYP4 family members process leukotriene B4 to 20-hydroxy-leukotriene B4 a less chemotactic agent, and produce derivatives of arachidonic acid which may have
important regulatory functions.
What Cyp metabolizes 50% of drgus
Important for drug drug interactions because one drug can inhibit a CYP and cause a build up or xenobiotics
Statins are cleared by CYP3A4 and need to be dosed carefully because 50% drugs use the system and compete so the one with the highest affinity will be cleared first.
Grapefruits inhibits CYP3A4 so statins can't be cleared and can cause liver damage.
Explain the effects of acetaminophen in CYP
Acetaminophen (tylenol) can be modififed through sulfuation and glucoronidation and excretted
Tynecol--- CYP2E1---> NAPQ1 (a toxon that needs to be quickly congugated)
CYP2E1 is induced by alcohol (ethanol) so the toxin builds up and without the glutathione to conjugate the cells can lyse and cause cell death.
WHt can inhibit CYT P450
CO! IT binds to the heme. This method is not selective for different cytochomres.
What inhibits CYP3A4
St John worts (hrebal wood), carbamazepine (anticonvulsant) rifampin (anti TB drug) Grapefruit juice
Explain what and why poor metabolizers happen
These are normal genetic polymorphisms based on the genes and alleles of P450 present.
This is important becaues poor metabolizers may have elevated levels of drug and be at risk for dose dependent toxicity