Cytochrome P-450 Monooxygenases in Oxidative Biotransformation

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Questions and Answers

What is the initial step in the role of cytochrome P-450 monooxygenases in oxidative biotransformation?

The reduced iron (Fe2+) cytochrome P-450-substrate complex binds to oxygen (O2).

One electron transfers from NADPH-dependent cytochrome P-450 reductase to the cytochrome P-450-substrate complex.

The substrate binds with the oxidized (Fe3+) state of cytochrome P-450 to form a cytochrome P-450-substrate complex. (correct)

Water is released from the latter intermediate to form an activated oxygen cytochrome P-450-substrate complex.

What is the outcome of the one electron transfer from NADPH-dependent cytochrome P-450 reductase to the cytochrome P-450-substrate complex?

The release of water from the latter intermediate.

The transfer of activated oxygen to the substrate.

The formation of a peroxide di-anion P-450 (Fe3+) substrate complex.

The reduction of (Fe3+) to (Fe2+). (correct)

What is the role of cytochrome P-450 reductase NADPH and cytochrome b5 reductase NADH in the process?

They release water from the latter intermediate.

They bind to oxygen (O2).

They transfer one electron to the cytochrome P-450-substrate complex. (correct)

They reduce the iron from (Fe2+) to (Fe3+).

What is the nature of the activated oxygen in the activated oxygen cytochrome P-450-substrate complex?

Highly electron deficient and a potent oxidizing agent. Signup and view all the answers

What is the final step in the process of oxidative biotransformation by cytochrome P-450 monooxygenases?

The transfer of activated oxygen to the substrate. Signup and view all the answers

What is the role of NADPH in the process of oxidative biotransformation by cytochrome P-450 monooxygenases?

To provide reducing equivalents. Signup and view all the answers

What is the type of reaction catalyzed by cytochrome P-450 monooxygenases in the oxidation of aromatic moieties?

Aromatic hydroxylation. Signup and view all the answers

What is the intermediate formed after the release of water from the peroxide di-anion P-450 (Fe2+) substrate complex?

An activated oxygen cytochrome P-450-substrate complex. Signup and view all the answers

What is one of the main goals of drug metabolism?

To change the structure of the drug and thus end its fitting to the receptor Signup and view all the answers

Which organ is rich in almost all drug-metabolizing enzymes?

The liver Signup and view all the answers

What is the result of the first pass effect on orally administered drugs?

The drugs are metabolized in the liver before reaching the systemic circulation Signup and view all the answers

What is the preferred site of hydroxylation in a mono-substituted benzene ring?

Para position Signup and view all the answers

What is the role of cytochrome P-450 in Phase I reactions?

To transfer an oxygen atom to the substrate Signup and view all the answers

What is the result of Phase I reactions?

The formation of a polar inactive moiety Signup and view all the answers

What happens when a compound contains two identical aromatic rings?

Oxidation of only one ring takes place Signup and view all the answers

What is the function of NADPH-dependant cytochrome P-450 reductase?

To reduce the substrate Signup and view all the answers

What influences the ease of hydroxylation in aromatic rings?

The presence of substituents attached to the aromatic ring Signup and view all the answers

What is the equation for Phase I reactions?

RH + NADPH + O2 + H+ = ROH + NADP+ + H2O Signup and view all the answers

In which type of aromatic rings does hydroxylation occur preferentially?

Electron-rich rings Signup and view all the answers

What is the purpose of creating a handle with which to bind a small polar molecule from the body?

To create a polar inactive moiety that can be eliminated from the body Signup and view all the answers

Which of the following groups is an electron-withdrawing group that slows down hydroxylation?

Cl Signup and view all the answers

Why are environmental pollutants considered highly toxic?

Because they are lipophilic and resistant to aromatic oxidation Signup and view all the answers

What is the result of the resistance to metabolism coupled to lipid solubility of environmental pollutants?

They persist in the body for a long time Signup and view all the answers

Which compound is an example of a deactivated aromatic ring that is slow or resistant to hydroxylation?

Clonidine HCl Signup and view all the answers

Study Notes

Drug Metabolism

Main goals of drug metabolism:
Change the structure of the drug to end its pharmacological activity
Increase the polarity of the drug
Create a handle for binding with a small polar molecule to form a polar inactive moiety for elimination from the body

Sites of Drug Metabolism

The liver is the primary site of drug metabolism due to its richness in drug-metabolizing enzymes and easy access for orally administered drugs (first-pass effect)

Phases of Drug Metabolism

Phase I (Functionalization Reactions): involves the breakdown of the drug molecule through oxidation, reduction, hydrolysis, and cyclization reactions
Example of Phase I reaction: RH + NADPH + O2 + H+ = ROH + NADP+ + H2O

Role of Cytochrome P-450 in Oxidative Biotransformation

Cytochrome P-450 monooxygenases play a crucial role in oxidative biotransformation
Steps involved in the process:
The substrate binds with the oxidized (Fe3+) state of cytochrome P-450 to form a cytochrome P-450-substrate complex
One electron transfer from NADPH-dependent cytochrome P-450 reductase to the cytochrome P-450-substrate complex reduces (Fe3+) to (Fe2+)
The reduced iron (Fe2+) cytochrome P-450-substrate complex binds to oxygen (O2)
The oxygen cytochrome P-450-substrate complex undergoes another one electron reduction by cytochrome P-450-reductase NADPH and/or cytochrome b5 reductase NADH to yield a peroxide di-anion P-450 (Fe3+) substrate complex
Water is released from the latter intermediate to form an activated oxygen cytochrome P-450-substrate complex
The activated oxygen is transferred to the substrate

Oxidation Reactions

Oxidation of aromatic moieties (aromatic hydroxylation):
Mono-substituted benzene rings usually undergo para hydroxylation (e.g., phenobarbitone)
If the compound contains two identical aromatic rings, oxidation of only one ring takes place (e.g., phenylbutazone)
Substituents attached to the aromatic ring may influence the ease of hydroxylation, with electron-rich rings being more susceptible to hydroxylation (e.g., diazepam)
Deactivated aromatic rings (containing electron-withdrawing groups) are slow or resistant to hydroxylation (e.g., clonidine HCl)
Environmental pollutants are resistant to aromatic oxidation due to the presence of numerous electron-withdrawing chlorine atoms on the aromatic ring

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Description

Explore the role of cytochrome P-450 monooxygenases in oxidative biotransformation, including the initial steps, electron transfer, and final outcome. Understand the functions of cytochrome P-450 reductase and cytochrome b5 reductase in this process.