Week 4 - Cytochrome p-450 Enzymes

Question 1

What do cytochrome p-450 enzymes contribute to?

Answer 1

The metabolism af about half of all medications*

Pretty important

Question 2

The enzyme Cytochrome-P450 drub metabolism exmamples (this is a veriy small list*** so many more drugs)

Answer 2

Examples of medicines …
Codeine (opiate to treat pain or relieve cough)
Acetaminophen
Cyclosporin A
Erythromycin

Question 3

Example of a cytochrome p-450 enzyme: CYP3A4

Answer 3

Superfamily of cytochrome p-450 enzymes

• Enzyme = Cytochrome P-450 3A4
• Gene = CYP3A4
• Expressed in the liver and intestines (i.e., involved in detoxification)

3A4 is an essential enzyme

Question 4

Codeine Metabolism - 2D6 Enzyme

Answer 4

• 2D6 is one enzyme that is required for the metabolism of codeine to morphine
• Most people are “extensive metabolizers” that allows them to effectively metabolize codeine to morphine
• People BENEFIT by Pain relief

Question 5

Pt balance of 3A4 and 2D6 on codein metabolism…

Answer 5

• You always have 3A4 …. but if the balance of 3A4 is too high compared to 2D6, then the bioavailability of codeine is reduced
• If too much 3A4, codeine does not metabolize to morphine
• 3A4 converts “codeine” to “norcodeine” which cannot be used by the body

Question 6

What are the different Types of metabolizers?

Answer 6

A “poor metabolizer” (PM) cannot metabolize codeine.. low 2D6, 3A4 converts codeine to norcodien

“Extensive Metabolizers” (EM) metabolize codeine

good balance - pt will metabolize correctly and can feel the pain relief

“Ultrarapid Metabolizer” metabolizes too quickly to be able to effectively benefit from the codeine

too much 2D6 and pt metabolizes it too fast (short pain relief)

Question 7

Poor metabolizers of Pain meds

Answer 7

• Someone who is a “poor metabolizer” has a genetic predisposition or polymorphism that blocks the metabolism of certain drugs
• They may over dose on less because it can not be metabolized

Question 8

Ultra rapic metabolizers

Answer 8

• “Ultra rapid metabolizers” may be less than 10% of the population
• They metabolize the drug too fast to gain any benefit from the medication
• Codeine-derivative medications provide no pain relief!!
• Ultra rapid metabolizers have a genetic predisposition or polymorphism that metabolizes certain drugs so quickly that there is no pain relief benefit.

Question 9

What are some factors that affect metabolism or balance of 2D6 and 3A4?

Answer 9

• Some medications that inhibit codeine metabolism
• …. like Quinidine (Quinidine Gluconate, Quinidine Sulfate)
• Medication that is used to correct disturbances in the rhythm of the heart (antiarrhythmic).
• Also used to treat malaria
• Grapefruit juice before you take some drugs can reduce your 3A4.

Question 10

QUESTION: How does reducing 3A4 (i.e., in comparison the 2D6 is higher) affect your ability to metabolize codeine?

Answer 10

df

Question 11

Summary 2D6 / 3A4 Balance

Answer 11

• More 2D6 than 3A4 = can convert codeine into morphine
• More 3A4 than 2D6 = cannot convert codeine (makes norcodeine)
• Grapefruit Juice = reduces 3A4
• Quinidine = reduces 2D6

Question 12

What is racial variability in CYP3A5?

Answer 12

CYPs and ability to metabolize some medications may be related to race (genome, hyploidtype)

For example, 3A5 occurs:
in 30% of Caucasians, Japanese, Mexicans
in 40% of Chinese
>50% of African Americans, Pacific Islanders, Southeast Asians, and Southwestern American Indians

Question 13

Populations Missing 2D6

Answer 13

5-10% of Caucasians are missing 2D6 enzyme activity making them “poor metabolizers” of codeine

Question 14

What is an essential enzyme??

Answer 14

CYP3A4

Question 15

Remember: What factors can influence how a person responds to medication?

Answer 15

Weight
Diet
Food in stomach
Fatigue
Age
Sun exposure
Physical condition / lack of exercise
Drug interactions (i.e., Cross reactivity, synergism)
Genetic make-up

Question 16

EGFR receptor in lung cancer…

Irressa or Tarceva used to treat lung cancer and possibly other cancers like head and neck.
Targeted Therapies

Answer 16

Either goes through apoptotic pathway or the proliferative pathway…

In cancer we want to block the proliferative pathway.

But only 10% responded..

Had great qualitity till drug became resistant..

Because of a deletion mutation** the people who had the mutation had a response to the drug**

SO. genetic test was very important

Question 17

Current method for gene sequencing to see if pts has the mutation…

Answer 17

• Formalin fix
• Cut an H and E
• Pathologist review and microdissection at least 50% tumor
• Deparafinize,
• isolate DNA, amplify and sequence

Question 18

Other methods..

Answer 18

• Melting technology
• PCR amplification and quantification
• Direct sequencing pyrosequencing

Question 19

Novel Biomarker Technology Underdevelopment

Answer 19

Requires new Methods

• RNA more targets for detection (vs DNA)
• No formalin fixation, blood test???
• Point of Care tests for cancer

Goal is to go from 2 weeks to 2 days for gene sequencing.

Question 20

Summary

Answer 20

• Personalized medicine is being used
• Targeted therapies in general, EGFR TKIs many more on the way
• Biomarker discovery

Question 21

What is an example of a drug that is showing progress?

Answer 21

Cetuximab Is an antibody (protein acceptable to human body) that attacks the receptors on cancer cell so that the cancer cell cannot multiply

Attacks oncoproteins such as EGFR
EGFR is a receptor on the cell’s surface
Found on many cancer cells (lung, CRC)
The EGFR protein gives improper signals to the cell to grow grow grow grow grow
If you give the patient cetuximab, the cetuximab goes to the EGFR protein and blocks its ability to send “grow grow grow” signals

Question 22

Objectives

Answer 22

Students will be able to describe the general role of the cytochrome p450 gene family

Students will be able to describe the 3 general types of metabolizers and the significance for pain management