Xenobiotic metabolism Flashcards
(63 cards)
What is the definition of biotransformation?
The process where the body attempts to convert lipophilic substances into more polar metabolites that can be excreted quicker
What is the primary result of biotransformation?
1.The parent molecule is transformed into a more polar metabolite, often by the addition of ionizable functional groups
2. Molecular weight and size are often increased
3. The excretion is facilitated, and hence elimination of the compound from the tissue
What are the consequences of metabolism?
- The biological half-life is decreased
- The duration of exposure is reduced
- Accumulation of the compound in the body is avoided
- The duration of the biological activity may be affected.
- Detoxification –> Less toxic/inactivation
- Toxification –> Can sometimes lead to more toxic compounds or another toxic effect
What characterize enzymes involved in metabolism?
Enzymes involved in metabolism are flexible and their substrate specificity is generally broad
What is the location of enzymes in biotransformation?
- Many are found in the smooth endoplasmic reticulum (SER)
- Some in the cytosol
- Few in other organelles e.g. mitochondria
What are the main types of phase 1 reactions?
1) Oxidation
2) Reduction
3) Hydrolysis
Which types of phase 2 reactions are there?
1) Glucuronidation
2) Sulfation
3) Glutathione conjugation
4) Conjugation with amino acids
5) Methylation
6) Acetylation
What is the purpose of phase 1 reactions
Alteration of the original molecule by exposing or introducing a functional group (-OH, -NH2, -SH, -COOH)
What is the purpose of phase 2 reactions
Conjugation of a polar group to the functional group –> Increases hydrophilicity (except for methylation and acetylation) –> facilitates excretion
Which enzymes are usually included in Phase 1 drug metabolism?
- Cytochrome P450s (CYP450 or CYPs)
- Alcohol dehydrogenase (ADH)
- Aldehyd dehydrogenase (ALDH)
- Esterases/amidases (hydrolases)
- Amine oxidase (MAO, FMO)
- Xanthine oxidase (XO) – a pyrine
- Alkylhydrazine oxidase
Where can phase 1 enzymes generally be found?
ER:
- CYPs
- FMO
- ADH/ALDH
- Epoxide hydrolase
- (Esterases/ amidases)
Mitochondria:
- MAO A/B
- ADH/ALDH
Cytosol:
- Esterases/ amidases
- ADH/ALDH
- Epoxide hydrolase
Which microsomal oxidation processes are involved in phase 1 reactions?
- Aromatichydroxylation o Aliphatichydroxylation o Alicyclic
- Heterocyclic
- N-,S- and O-dealkylation o N-oxidation
- N-hydroxylation
- S-oxidation
- Desulfaration
- Deamination
- Dehalogenation
Which non-microsomal oxidation processes are involved in phase 1 reactions?
1) Amine oxidation
2) Alcohol and aldehyde oxidation
3) Peroxidases
Describe the catalytic cycle of the cytochrome P-450 monooxygenase system
- Addition of substrate to enzyme
- Donation of an electron
- Addition of oxygen and rearrangement
- Donation of a second electron and loss of water
What enzymes are involved in amine oxidations and what are their main characteristics?
Monoamine oxidases (MAO):
- Located in mitochondria
- Oxidative deamination of primary, secondary and tertiary amines
Diamine oxidases:
- Located in the liver and other tissue
- Soluble enzyme
- Is mainly involved in the metabolism of endogenous compounds such as the aliphatic diamine putrescine
Alcohol dehydrogenase:
- Is a cytosolic enzyme (soluble fraction)
- Located in the liver and also kidney and lungs
- Coenzyme NAD (sometimes NADP - slower)
Aldehyde dehydrogenase:
- Located in the mitochondria (ALDH2)
Other enzymes:
Molybdenum hydroxylases
Xanthine oxidase
Aldehyde oxidase
Peroxidases
- Are dependent on co-oxidation
What enzymes are involved in reduction
Enzymes who catalyzes reduction:
* Gut bacterial azo- and nitro-reductase
* Cytochrome P-450 NADPH reductase –> works in low conditions of oxygen
* FAD alone (is not an enzyme)
(CYPs are also capable of reduction)
Reactions are dependent on:
- NAD(P)H
Inhibited by:
- O2
What enzymes are involved in hydrolysis
1) Esterases
2) Amidases
3) Epoxide hydrolases
4) Peptidases
(CYPs are also capable of hydrolysis)
Types of esterases
Class A)
A-esterases: Hydrolyze organophosphates (arylesterases, paraoxonase). These are not inhibited by phosphate triesters.
Class B)
B-esterases: Inhibited by organophosphates e.g. paraoxon (include carboxylesterases, cholinesterases, arylamidases)
Class C)
C-esterases: Are acetylesterases. These are not inhibited by paraoxon and the preferred substrates are acetyl esters.
What are the steps and the product of glucuronidation (glucuronic acid conjugation)?
- Conjugation with UDP-Glucuronic acid catalyzed by UDP-glucuronosyl transferase (UGT)
2) Glucuronic acid is afterwards converted into hydroxyl, carboxyl, nitrogen and sulfur
Which enzyme catalyze sulfation
Sulfotransferase (SULT)
- with the cofactor 3’-phosphoadenosyl-5-phosphosulfate (PAPS):
What are the product of sulfation?
Highly water soluble sulfate esters
How can PAPS be depleted
When large amount of foreign compound conjugated with sulfate (e.g. paracetamol) is administered
Which enzyme catalyze glutathione conjugation
Glutathione-S-transferases (GST)
Describe the structure of glutathione
Glutathione is a tripeptide composed of:
1) Glutamat
2) Cysteine
3) Glycine
