Metabolism of Xenobiotics

Question 1

Chemical substances that are foreign to an organism’s metabolism

It can potentially cause harm. (NOT part of normal food)

Includes: drugs, environmental pollutants, and other chemicals that are not naturally produced or expected to be found within an organism’s body.

Answer 1

Xenobiotics

Question 2

Most versatile enzyme for metabolism of xenobiotics

Answer 2

Monooxygenase
(Cytochrome P450)

Question 3

Metabolism of Xenobiotics is mainly in the

Answer 3

liver

Question 4

Enumerate the importance of metabolizing xenobiotics

Answer 4

1. To Activate (from inactive form)
2. To Increase polarity - becomes water soluble and can be excreted
3. For excretion - via urine (kidneys) or bile (GIT)
4. For detoxification

Question 5

Definition: Prodrugs

Answer 5

Xenobiotics that enter the body in and inactive form which needs to be metabolized inorder to have the desired effects

(e.g. antibiotics)

Question 6

Phases of Xenobiotic Metabolism

Answer 6

• Phase 1 - make compounds more reactive
• Phase 2 - make compounds more polar for excretion

Question 7

What are the reactions involved in PHASE 1 metabolism of xenobiotics

Answer 7

Major reaction: Hydroxylation catalyzed via cytochrome P450

Other reactions:
- deamination
- dehalogenation
- desulfuration
- epoxidation
- peroxygenation
- reduction
- hydrolysis catalyzed by esterases of non-P450 catalyzed

*most Phase 1 reactions are removal of a functional group in the compound to make more active while phase 2 adds

Remember 2 is MORE than 1, 2 adds, 1 removes*

Question 7

What are the reactions involved in PHASE 1 metabolism of xenobiotics

Answer 7

Major reaction: Hydroxylation catalyzed via cytochrome P450

Other reactions:
- deamination
- dehalogenation
- desulfuration
- epoxidation
- peroxygenation
- reduction
- hydrolysis catalyzed by esterases of non-P450 catalyzed

*most Phase 1 reactions are removal of a functional group in the compound to make more active while phase 2 adds

Remember 2 is MORE than 1, 2 adds, 1 removes*

Question 8

What are the reactions involved in PHASE 2 metabolism of xenobiotics

Answer 8

Conjugation Reactions

Five types of phase 2 reactions:
1. glucuronidation
2. sulfation
3. conjugation with glutathione
4. acetylation
5. methylation

Note: especially for hydrophobic xenobiotics, when not converted will persist in adipose tissue

Question 9

5 TYPES OF PHASE 2 REACTIONS:

The most common conjugation reaction

Answer 9

Glucuronidation

• Glucoronyl Donor: UDP-glucuronic acid
• Enzyme: glucuronosyltransferases (found in both ER and cytosol)

Question 10

5 TYPES OF PHASE 2 REACTIONS:

Xenobiotics that undergo gulcuronidation

Answer 10

• steroid hormones
• 2-acetylaminofluorene (carcinogen in dyes and inks)
• aniline
• benzoic acid (preservatives)
• meprobamate (anxiyotitic and sedative drugs)
• phenols

Question 11

5 TYPES OF PHASE 2 REACTIONS:

Common phase 2 reaction for alcohols, arylamines, and phenols

Answer 11

Sulfation

• Sulfate Donor: adenosine 3’-phosphate-5’-phosphosulfate (PAPS) or active sulfate

Question 12

5 TYPES OF PHASE 2 REACTIONS:

A tripeptide consisting of **glutamic acid, cysteine, **and glycine

Functions to:
* transport amino acids
* decomposition of toxic hydrogen peroxide

Answer 12

Glutathione

Question 13

5 TYPES OF PHASE 2 REACTIONS:

Enzyme used for conjugation with glutathion reaction

Forms glutathione-S-conjugates that are excreted through urine and bile

Answer 13

Glutathione S-transferases

• very active in the liver
• also bind to number of substrates that are not xenobotics

Question 14

5 TYPES OF PHASE 2 REACTIONS:

Common phase 2 reaction for tuberculosis drug: isoniazid

Answer 14

Acetylation

• Acetyl Donor: Acetyl CoA
• Enzyme: acetyltransferases (present in the liver)

Individuals can be classified as slow acetylators or fast acetylators
- slow acetylator individuals are more subject to toxic effects of isoniazid

Question 15

5 TYPES OF PHASE 2 REACTIONS:

Reaction catalyzed by methyltransferases where S-adenosylmethionine is the donor for conjugation

Answer 15

Methylation

Question 16

Family of very versatile enzymes that are hemoproteins (heme-containing)

Found in all cells but more abundant in the liver

Catalyzed reaction involves NADPH

Answer 16

Monooxygenase or Cytochrome P450

Question 17

Phenobarbital

Answer 17

first step treatment in uncomplicated seizures

Question 18

Warfarin

Answer 18

blood thinner or anticoagulant

Question 19

Nomenclature for Cytochrome P450 enzymes

40% similarity in AA sequence will be classified as part of the family of cytochrome P450 enzymes

Answer 19

• Root name: CYP
• Family: number
• Subfamily: capital letter

ex. CPY1A1

Question 20

Factors affecting the metabolism of xenobiotics

Answer 20

• species
• genetic factors
• age
• sex
• various diseases

Question 21

Responses to metabolism of xenobiotics

Answer 21

Question 22

Small molecules that can bind to larger molecules, such as proteins or nucleic acids, and cause an immune response in the body.

Often responsible for allergic reactions to various substances, such as drugs, cosmetics, and chemicals.

Answer 22

Haptens

Haptens alone cannot generate an immune response; they need to bind to a larger carrier molecule in order to become immunogenic. Once the hapten-carrier complex is formed, the immune system can recognize it as foreign and mount an immune response.

Question 23

Study of what the body does to the drug

Answer 23

Pharmacokinetics