Lecture 5

Question 1

CYP450

Answer 1

powerful detox system
substrates are unusual chemicals like poisons, drugs, carcinogens
adds oxygen to flush from body, first line of D against toxins
in steroid hormone synthesis, polyunstaturated FA metabolism
superfamilies in animals plants funi protozoa
humans have 18 families usually CYP1-4

Question 2

CYP450 functions

Answer 2

enzymatic function: insert OH from O2 – 1 O to product and 1 O to water. this causes product to be more hydrophillic and better at detoxyfying – requires heme ion for oxidation
biol functions: maintaining amount of drug in body
metabolism: repsonsible for 65-70% pf clearance drugs
CYP3A4 estimated act on 30-50% of known drugs

Question 3

CYP450 structure

Answer 3

structure is well conserved: conformational change occurs upon ligand binding — heme site for oxidation – substrate binds in the center where heme binds

Question 4

CYP location

Answer 4

memebrane associated transport systems in ER and mitocondria O2 activated and cleared
reduction of P450 heme Fe NADPH is electron source

Question 5

CYP450 oxidize exogenous compounds (xenobiotics)

Answer 5

lypophillic xenobiotics: theapeutic drugs, contaminants — promotes elimation –CYP3A4 responsible for poor biolavail of some drugs
P450s are less discriminating – perform multiple reactions, regioselective substances can be hydroxylated

Question 6

Oxygenation of endogenous compounds

Answer 6

catalyze multiple reactions – pathways for steroid hormones, one P450 can catalyze multiple steps

Question 7

Drug-drug interaction

Answer 7

unintended effects due to other drug altering P450 activity
induction of P450 can lead to increase of inhibition/decrease of drug plasma level – porblematic for drugs requiring high control of plasma levels

Question 8

CYP450 induction

Answer 8

steroid biosynthetic P450 induced by adrenocortiotropic hormone
increased P450 of one drug can adversely affect metabolism of second drug – induced expression increases P450 level and enzymatic processing of compounds by that P450
unregulated CYP3A4 can increase rate of metabolism of many drugs cleared through liver
xenobiotics and certain drugs inhibit CYP3A4 enzymatic activity

Question 9

Acetaminophen induced liver toxicity

Answer 9

NAPQI is generated from acetominophen being metabolized by CYP2E1
NAPQI is normally conjugated w/ glutathione to generate non toxic form, but high doses of aceto can deplete glutathione pool
large doses of acetominophen increase NAPQI and liver damage – 35% of liver failure is due to aceto poisoning
alcohol also induces CYP2E1 which can increase NAPQI