Metabolism and Biotransformation, Phase I

Question 1

Basics of biotransformation?

Answer 1

1. .) Stereo-specific – enzyme specificity
2. ) Genetic polymorphism – altered activity
3. ) Occur primarily in the liver - carried out in a variety of locations
4. ) Wide species differences - caution

Question 2

Phase I reactions?*

Answer 2

Types of reactions:
- Hydrolysis
- Reductions
- Oxidations
Biotransformations can activate or detoxify xenobiotics*
Many xenobiotics metabolized by P450 enzymes in liver**

Question 3

Phase II reactions?*

Answer 3

1. .) Biotransform products of Phase I metabolism
2. ) Produce more water soluble metabolites that aid in urinary elimination
3. ) Generally result in detoxification or elimination

Question 4

Phase I reactions: Hydrolysis - Major types?

Answer 4

1. ) Carboxylesterases, pseudocholinesterases and paraoxonase
2. ) Peptidases
3. ) Epoxide hydrolases
   - Important means to detoxify many epoxide metabolites into diols

Question 5

Reduction types?

Answer 5

1. .) Azo and nitro reduction
2. ) Carbonyl and disulfide reduction
3. ) Sulfoxide and quinone reduction
4. ) Reductive dehalogenation

Question 6

Is the following a hydrolysis or oxidation reaction?

Answer 6

See lecture notes

Hydrolysis reactions add water**

Question 7

What can looking at a chemical structure tell you?

Answer 7

If it has a reactive component, it may have toxic effects

- Reactive oxygen species can attack systems, damages proteins

Question 8

Alcohol dehydrogenases (ADH)?

Answer 8

Oxidation reaction;

• Wide range of specificity, present in many tissues
• Competitive inhibition by other alcohols
• Major cofound in the workplace.

Question 9

Aldehyde dehydrogenase (ALDH)?

Answer 9

Oxidation reaction (adds H2O);

• Wide range of specificity, present in many tissues
• Usually the rate limiting step in alcohol metab.
• Genetic polymorphism

Question 10

Molybdenum hydrolases?

Answer 10

Oxidation reaction; two major types (both are flavoproteins (FAD));
- Aldehyde oxidases
- Xanthine dehydrogenase/oxidase
Mechanism:
- Exchange of electrons from Mo with substrate and reoxidation, oxygen comes from water, not 02

Question 11

Monoamine, diamine polyamine oxidase?

Answer 11

1. .) Oxidative deamination
2. ) Uses FAD
3. ) H2O2 produced, oxidative stress

Question 12

What is peroxidase-dependent cooxidation?

Answer 12

coupling of H2O2 with lipid hydroperoxidases to oxidize other substrates
- Important enzyme in tissues, activation of benzene to active metabolite

Question 13

Flavin monooxygenases (FMO)?

Answer 13

1..) Microsomal enzymes requiring NADPH
and Oxygen
2.) Flavoproteins that oxidize N, S, P atoms
3.) Requires Flavin adenine dinucleotide (FAD)

Question 14

What is the most important biotransformation system?

Answer 14

The cytochrome P450 system

- Identifed in 1950’s as a spectral peak at 450 nm upon reoxidation of an enzyme preparation with CO

Question 15

Cytochrome P450 system characteristics?*

Answer 15

Requires NADPH and FAD
Inducible** - many drugs and chemicals induce the metabolic activity of CYP 450
Polymorphic** – Exist in different
phenotypes resulting in different rates of
metabolism in the same species