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57 terms

Phase I Metabolism

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Competitive inhibitor
competition for the enzyme is dependent on the concentration of the substrate and the inhibitor
Non-competitive inhibitor
competition for the enzyme is not dependent on the concentration of the enzyme
Suicide inhibitor
binds to nitrogens in the heme moiety and destroys the heme and CYP450 activity
Most abundant CYP isoform?
CYP3A
What CYP families are the most relevant to drug metabolism?
CYP1, CYP2, CYP3
What subfamilies make up the CYP1 family?
CYP1A and CYP1B
What percentage of drugs do the three main CYP families metabolise?
80%
What are the major subfamilies of the CYP2 isoform?
CYP2A, CYP2B, CYP2C, CYP2D and CYP2E
What subfamily makes up the CYP3 family?
CYP3A
What CYP isoforms are responsible for the bioactivation of most carcinogens?
CYP1A1/2, CYP1B1, CYP2E1 and CYP3A
Is CYP1A1 or CYP1A2 constitutively expressed in the liver? Where is the other one expressed?
CYP1A2
CYP1A1 is expressed in the lung, intestine and skin
Describe the mechanism through which induction of CYP1A1 occurs.
depression of the repressor protein that suppresses CYP1A1 activity and activation of CYP1A1 gene transcription
Is there high or low homology between CYP1A1 and CYP1A2?
High
What accounts for the low constitutive levels of CYP1A1?
Repressor protein
Name the potent inducers of CYP1A1
TCDD, 3-methylchloranthrene and beta-naphthoflavone
What receptor is CYP1A1/2 regulated by?
aryl hydrocarbon receptor (AhR)
What enzyme is constitutively expressed in steroid responsive tissue?
CYP1B1
Where is CYP1B1 expressed?
uterus, breast, prostate, testis, ovary, adrenal cortex
What CYP is found to be elevated in various cancers?
CYP1B1
What enzyme causes 4-hydroxylation of estradiol?
CYP1B1
What is responsible for both constitutive and inducible expression of CYP1B1?
aryl hydrocarbon receptor
Name three inducers of CYP1B1
TCDD, ACTH and polycyclic aromatic hydrocarbons
What percentage of clinically used drugs are metabolised by CYP2D6?
20-25%
How many amino acids does CYP2D6 contain?
497
Does CYP2D6 have high or low hepatic abundance?
low
What is CYP2D6 inhibited by?
Paroxetine
What CYP is not regulated by environmental agents or hormones?
CYP2D6
What CYP has a high affinity for alkaloids? What do alkaloids contain?
CYP2D6
Nitrogen
What are the substrates of CYP2D6?
lipophilic bases with a nitrogen atom
Where does hydroxylation of CYP2D6 substrates occur?
5-7 angstroms from the nitrogen atom
What CYP exhibits extensive polymorphisms?
CYP2D6
What are the four results of a genetic polymorphism in the CYP2D6 enzyme?
ultrarapid metaboliser, extensive metaboliser, intermediate metaboliser and poor metaboliser
What is the normal type of CYP2D6 metaboliser?
extensive metaboliser
What do the levels of CYP2E1 change according to?
food intake (endogenous control)
What occurs during CYP2E1 induction?
protein stabilisation - shutdown degradation of protein
Name some inducers of CYP2E1
fasting, diabetes, ethanol, acetone, isoniazid, pyridine and pyrazole
Name some inhibitors of CYP2E1
diallyl sulfide, chlormethiazole, CCl4
What does CYP2E1 metabolise?
small hydrocarbons, alcohols, anesthetics, nitrosamines and aromatics
What can CYP2E1 alone cause the formation of? Why? Example
ROS causing oxidative stress
CYP2E1 is an easily coupled enzyme
Ethanol causes oxidative stress through CYP2E1 induction
What does overexpression of CYP2E1 in hepatic cells increase?
intracellular hydrogenperoxide (40-50%)
What is the physiological role of CYP2S1?
unknown
What does CYP2S1 metabolise?
bioactive lipids including prostaglandins and retinoids
Where is CYP2S1 located?
Extra-hepatic and in epithelial cells
What cancer drug is CYP2S1 involved in the activation of?
banoxantrone (AQ4N)
What are the allelic variations of CYP2S1?
CYP2S1*2,3,4,5
What are the CYP3A isoforms found in humans?
CYP3A4,5,7
What percentage homology is there between all the CYP3A isoforms?
90%
Where is the CYP3A enzyme located?
Liver, kidney, intestine
What enzyme makes up 50% of the liver enzyme levels?
CYP3A
How much greater are CYP3A levels in females compared to males?
24%
Name some inducers of the CYP3A enzyme
dexamethasone, corticosteroids, vitamin A, phenytoin
Name some inhibitors of CYP3A
naringenin, ketoconazole, saquinivir, erythromycin
What carcinogens does CYP3A bioactivate?
aflatoxin, nitropyrene, nitrochrysene
What regulates CYP3A gene transcription?
pregnane X receptor (PXR)
What superfamily is pregnane X receptor part of?
orphan nuclear receptor superfamily
What other receptor does the pregnane X receptor for a heterodimer with?
retinoid X receptor
What other CYPs is PXR thought to regulate?
CYP2C8, 2C9, 2C19