Biochem Flashcards
Why do we need the cytochrome p450 system?
Plants contain hydrophobic toxins (Xenobiotics) to stop them being eaten, but we eat them anyway (tea leaves, caffeine, cacao, citrus, broccoli, cabbage, brussel sprouts, kale etc).
We absorb the C-rich hydrophobic molecules and retain them in our fatty tissue, but they can be toxic if they build up to high levels.
CP450 system metabolises them to make them more soluble so they can be excreted via the renal system.
Xenobiotic
Hydrophobic toxic molecule that we don’t make ourselves
Phase I detoxification
Hydroxylation, epoxidation, dealkylation, oxidation reactions catalysed by CP450
Add OH onto molecule to make it more soluble so it can be excreted via kidneys
Phase II detoxification
Adds a sugar onto the OH created by the phase I detoxification reaction to make the cpd EVEN MORE soluble.
How is caffeine metabolised?
CYP142 removes a methyl group or adds a ketone to make it more soluble
Most important CYP in human for drug metabolism
CYP3A4
Most important CYP in humans in terms of polymorphisms . What does this mean?
CYP2D6
Means even in people with the same subform of this enzyme will possess variable enzyme activity; the same drug (any cpd metabolised by this enzyme) will have different effects in different people.
What does it mean when it is said that “CYPs are inducible”
On exposure to certain substrates, that CYP expression is induced/increased (the level of that enzyme will increase)
Where does CYP activity mainly take place? (organ and organelle)
ER within hepatocytes of the liver
What is the biochemical reaction that occurs when CYT P450 binds to it’s substrate?
- Substrate binds to active site.
- NADPH CYT p450 reductase in ER membrane next to CYTp450 oxidises NADPH
- releases 2e- and 1H+
- e-s reduce the flavin (only one e- comes out of the flavin)
- reduced flavin reduces CYT p450 which then converts Fe3+ to Fe2+
- Reduces one of the 2 atoms of molecular oxygen to water????
How is CYT p450 similar to Hb?
How are they different?
Both contain heme, which contains Fe which can alternate between Fe2+ and Fe3+
In CYT p450 cysteine is anchored to Fe (heme) whereas in Hb histamine is anchored to heme
Give an example of how CYP450 can also generate toxins
Aspergillus fungus on peanuts is converted to Aflatoxin B1 which becomes toxic when acted upon by CYP450 -> becomes a mutagen (reacts w DNA)
What is a poor metaboliser?
CYP polymorphism
Homozygous for 1 deficient CYP allele or heterozygous for 2 different deficient alleles
4% of caucasians
What is an intermediate metaboliser?
CYP polymorphism
heterozygous for one deficient allele or carry 2 alleles that cause reduced activity
32%
What is an extensive metaboliser?
CYP polymorphism
2 wild-type alleles
NORMAL levels of CYPs
55% of us
ultra rapid metabolisers
CYP polymorphism
multiple gene copies - CYP450 is more active
9% of us
What are possible consequences of underactive/deficient CYPs?
Give an example
Ineffective action of drugs (Codeine has to be metabolised by CYP2D6 to morphine in order to give pain relief so poor metabolisers will have no pain relief)
Not metabolised/broken down
Overdoses (drugs reaching too high [] can have toxic side-effects)
What are possible consequences of hyperactive CYPs?
example of drugs commonly effected by this
Ineffective due to too low [drug]
Certain antidepressants and antipsychotics
Functions of mononuclear phagocyte system. Where is it? Main role?
In spleen. Main role to identify and remove old/damaged RBCs from circulation (90% of recycling)
+ FOrm Abs, plasma proteins, bile pigments
In embyro form new RBCs and WBCs
where in the gut are cholesterol, bile salts, and gets absorbed>
Upper gut: fats
Lower gut: bile salts and cholesterol
What are the components of bile?
Water
Bile pigment (breakdown products (bilirubin diglucoronide) of Hb)
Bile acids/salts (cholesterol derivatives)
Free cholesterol
FA
Lecithin (phospholipids)
Inorganic salts
What are bile salts composed of, what do they come from?
Derivatives of cholesterol
Made of a mixture of unconjugated bile acids (pka5), glycoconjugates (pka3.7) and tauroconjugates (pka1.5)
Lower pka, more acidic and hydrophilic.
Overall highly soluble for excretion!
What is the serum marker of pancreatitis? Acute specifically?
Elevated serum lipase and/or amylase.
Acute is especially high lipase.
What are the 2 main causes of pancreatitis?
Gallstones -> block pancreatic duct/gall duct -> bile activates digestive enzymes: digestive juices back up into pancreas -> autodigestion of pancreas -> severe pain!
Alchoholism (2/3 cases) -> direct toxicity to pancreas -> inflammation and premature activation of pancreatic digestive enzymes -> ultimate necrosis and fibrosis
