Intro to Pharmacology and Toxicology Topics   

Phase 1 Reactions

Phase 1 reactions include oxidations and reductions via microsomal and nonmicrosomal enzymes, and hydrolysis. The many microsomal oxidations by cytochrome P450 are discussed in the next page. Nonmicrosomal oxidations include alcohol and aldehyde oxidation, purine oxidation and oxidative deamination.

Alcohol dehydrogenase is located in the liver cytosol and catalyzes the conversion of alcohols to acetaldehydes using NAD+ as cofactor.

Aldehyde dehydrogenase, also in liver cytosol, metabolizes acetaldehydes to yield organic acids:

Xanthine oxidase, an important enzyme in purine metabolism, also metabolizes xenobiotics with a purine structure.

Monoamine oxidases (MAO) in the mitochondria catalyze the oxidation of primary amines. Liver MAOs will also act on secondary and tertiary amines. This enzyme acts on endogenous amines as well as xenobiotics.

Flavin-containing monooxygenase (FMO) is a microsomal enzyme that catalyzes oxidation at nitrogen, sulfur and phosphorous atoms:
                                                                     O
                                               FMO            
RSCH3   + NADPH     RSCH3  +   NADP+

Some example substrates are nicotine, sulindac and taxmoxifen.

FMO requires NADPH. It is functionally different from CYP450 because the active oxygenating species exists stable within the protein in the absence of substrate. Other differences between the two enzymes are: heat and detergents destroy CYP but not FMO, FMO is active at high pH (~8.5), and clotrimazole can inactivate CYP.

Phase 1 reduction reactions include azo or nitro reduction by P450 and other enzymes, and reductive dealogenation. Nitro groups are reduced by microsomal reductases (?? same as P450??):

P450 and enzymes from gut microflora can reduce azo groups to yield two amines:

Halogen atoms may be removed from xenobiotics by oxidative or reductive catalysis of P450. The dealogenation of carbon tetrachloride, an important environmental toxicant, undergoes a P450 catalyzed reduction to yield a trichloromethyl radical that later abstracts a hydrogen atom from the lipid membrane of the endoplasmic reticulum to yield chloroform and initiate oxygen-consuming lipid peroxidation:

Acetylcholinesterase, plasma cholinesterases and carbonic anhydrase catalyze the hydrolysis of esters. Some amides (-CONH-) are also hydrolyzed but much slower than esters and not at all in plasma.

Continue to "Cytochrome P450 Enzymes" or take a quiz: [Q1].

Back to Basics: Degradation of Nucleotides (Biochemistry)
                            Autonomic Pharmacology (Medical Pharmacology)

Advance Topics: Cholinesterase Inhibitors (Medical Pharmacology)

Need more practice? Answer the review questions below (after sponsor).

1- List 4 types of Phase 1 reactions.

2- List 4 types of nonmicrosomal oxidation reactions.

3- What is the location and activity of alcohol dehydrogenase? Give an example substrate.

4- What is the location and activity of aldehyde dehydrogenase? Give an example substrate.

5- What is the activity of xantine oxidase on xenobiotics? Give an example substrate.

6- What is the activity of mitochondrial MAO? Give an example substrate.

7- What is the activity of liver MAO?

8- What is the location and activity of FMO? Give an example substrate.

9- List 4 differences between FMO and cytochrome P450.

10- List 3 Phase 1 reduction reactions.

11- What is the activity of microsomal reductase (??may be the same as P450??)?

12- How are azo groups reduced?

13- What is reductive dealogenation?

14- Describe the reductive dealogenation of carbon tetrachloride and fate of the metabolite.

15- How does ester hydrolysis occur?

Continue scrolling to answers below (after sponsor).

Hey! DON'T PEEK!!! Finish the questions fist!

1- List 4 types of Phase 1 reactions.
microsomal oxidations
microsomal reductions
nonmicrosomal oxidations
nonmicrosomal reductions
hydrolysis

2- List 4 types of nonmicrosomal oxidation reactions.
alcohol oxidation
aldehyde oxidation
purine oxidation
oxidative deamination

3- What is the location and activity of alcohol dehydrogenase? Give an example substrate.
Located in the liver cytosol, catalyzes the conversion of alcohols to acetaldehydes using NAD+ as cofactor. Example: ethanol.

4- What is the location and activity of aldehyde dehydrogenase? Give an example substrate.
Located in the liver cytosol, catalyzes the conversion of acetaldehydes to organic acids using NAD+ as cofactor. Example: acetaldehyde.

5- What is the activity of xantine oxidase on xenobiotics? Give an example substrate.
Oxidizes xenobiotics with a purine structure adding an oxygen atom to the 5-bond ring. Example: theophylline

6- What is the activity of mitochondrial MAO? Give an example substrate.
Catalyze the oxidation of primary amines to yield an aldehyde. Example: seratonin.

7- What is the activity of liver MAO?
Catalyze the oxidation of primary, secondary or tertiary amines to yield an aldehyde.

8- What is the location and activity of FMO? Give an example substrate.
Microsomal enzyme that catalyzes the oxidation of hydrogen, sulfur and phosphorous atoms. Examples: nicotine, sulindac, taxmoxifen.

9- List 4 differences between FMO and cytochrome P450.
the active oxygenating species in FMO exists within the protein in the absence of substrate
heat and detergents destroy cytochrome P450
FMO is active at high pH
clotrimazole inactivates cytochrome P450

10- List 3 Phase 1 reduction reactions.
azo reduction
nitro reduction
reductive dealogenation

11- What is the activity of microsomal reductase (??may be the same as P450??)?
Reduces nitro groups (NO2) to an amine group (NH2)

12- How are azo groups reduced?
By P450 or gut microflora enzymes, yielding two amines.

13- What is reductive dealogenation?
Halogen atoms may be removed from xenobiotics by reductive catalysis of P450, yielding a free radical.

14- Describe the reductive dealogenation of carbon tetrachloride and fate of the metabolite..
Is catalyzed by P450 and yields a trichloromethyl radical that later abstracts a hydrogen atom from the lipid membrane of the endoplasmic reticulum to yield chloroform and initiate oxygen-consuming lipid peroxidation.

15- How does ester hydrolysis occur?
Catalyzed by either acetylcholinesterase, plasma cholinesterase or carbonic anhydrase, yielding two alcohols.

Sponsor (again...):