Metabolism of Xenobiotics Flashcards
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.
Xenobiotics
Most versatile enzyme for metabolism of xenobiotics
Monooxygenase
(Cytochrome P450)
Metabolism of Xenobiotics is mainly in the
liver
Enumerate the importance of metabolizing xenobiotics
- To Activate (from inactive form)
- To Increase polarity - becomes water soluble and can be excreted
- For excretion - via urine (kidneys) or bile (GIT)
- For detoxification
Definition: Prodrugs
Xenobiotics that enter the body in and inactive form which needs to be metabolized inorder to have the desired effects
(e.g. antibiotics)
Phases of Xenobiotic Metabolism
- Phase 1 - make compounds more reactive
- Phase 2 - make compounds more polar for excretion
What are the reactions involved in PHASE 1 metabolism of xenobiotics
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*
What are the reactions involved in PHASE 1 metabolism of xenobiotics
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*
What are the reactions involved in PHASE 2 metabolism of xenobiotics
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
5 TYPES OF PHASE 2 REACTIONS:
The most common conjugation reaction
Glucuronidation
- Glucoronyl Donor: UDP-glucuronic acid
- Enzyme: glucuronosyltransferases (found in both ER and cytosol)
5 TYPES OF PHASE 2 REACTIONS:
Xenobiotics that undergo gulcuronidation
- steroid hormones
- 2-acetylaminofluorene (carcinogen in dyes and inks)
- aniline
- benzoic acid (preservatives)
- meprobamate (anxiyotitic and sedative drugs)
- phenols
5 TYPES OF PHASE 2 REACTIONS:
Common phase 2 reaction for alcohols, arylamines, and phenols
Sulfation
- Sulfate Donor: adenosine 3’-phosphate-5’-phosphosulfate (PAPS) or active sulfate
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
Glutathione
5 TYPES OF PHASE 2 REACTIONS:
Enzyme used for conjugation with glutathion reaction
Forms glutathione-S-conjugates that are excreted through urine and bile
Glutathione S-transferases
- very active in the liver
- also bind to number of substrates that are not xenobotics
5 TYPES OF PHASE 2 REACTIONS:
Common phase 2 reaction for tuberculosis drug: isoniazid
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
5 TYPES OF PHASE 2 REACTIONS:
Reaction catalyzed by methyltransferases where S-adenosylmethionine is the donor for conjugation
Methylation
Family of very versatile enzymes that are hemoproteins (heme-containing)
Found in all cells but more abundant in the liver
Catalyzed reaction involves NADPH
Monooxygenase or Cytochrome P450
Phenobarbital
first step treatment in uncomplicated seizures
Warfarin
blood thinner or anticoagulant
Nomenclature for Cytochrome P450 enzymes
40% similarity in AA sequence will be classified as part of the family of cytochrome P450 enzymes
- Root name: CYP
- Family: number
- Subfamily: capital letter
ex. CPY1A1
Factors affecting the metabolism of xenobiotics
- species
- genetic factors
- age
- sex
- various diseases
Responses to metabolism of xenobiotics
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.
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.
Study of what the body does to the drug
Pharmacokinetics
