Phase I Metabolism

Created by mccdo684 

Upgrade to
remove ads

57 terms

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

Please allow access to your computer’s microphone to use Voice Recording.

Having trouble? Click here for help.

We can’t access your microphone!

Click the icon above to update your browser permissions above and try again

Example:

Reload the page to try again!

Reload

Press Cmd-0 to reset your zoom

Press Ctrl-0 to reset your zoom

It looks like your browser might be zoomed in or out. Your browser needs to be zoomed to a normal size to record audio.

Please upgrade Flash or install Chrome
to use Voice Recording.

For more help, see our troubleshooting page.

Your microphone is muted

For help fixing this issue, see this FAQ.

Star this term

You can study starred terms together

NEW! Voice Recording

Create Set