Med Chem Exam 2

The primary purpose of drug metabolism from the body’s perspective is to:

a. Enhance drug potency

b. Convert drugs into more lipophilic forms

c. Convert drugs into more hydrophilic metabolites for excretion

d. Promote drug reabsorption in the kidney

c. Convert drugs into more hydrophilic metabolites for excretion

Lipophilic drugs can be reabsorbed through renal tubules because they:

a. Are too large to pass through membranes

b. Can cross biological membranes easily

c. Are highly polar

d. Bind strongly to plasma proteins

b. Can cross biological membranes easily

The main site of drug metabolism in the human body is the:

a. Kidney

b. Brain

c. Liver

d. Lung

c. Liver

Phase I reactions are generally known as:

a. Conjugation reactions

b. Functionalization reactions

c. Hydrolytic reactions only

d. Detoxification reactions only

b. Functionalization reactions

Which of the following is a phase II reaction?

a. Oxidation

b. Reduction

c. Hydrolysis

d. Glucuronidation

d. Glucuronidation

Cytochrome P450 (CYP450) enzymes are:

a. Found in the cytosol

b. Membrane-bound hemeproteins found in the endoplasmic reticulum (ER)

c. Exclusively found in the mitochondria

d. Protein transporters for xenobiotics

b. Membrane-bound hemeproteins found in the endoplasmic reticulum (ER)

CYP450 enzymes primarily use which co-factor to receive electrons for oxidation reactions?

a. NAD+

b. NADPH

c. ATP

d. FAD

b. NADPH

Which isoform is responsible for the majority of hepatic drug metabolism?

a. CYP2D6

b. CYP2C9

c. CYP3A4

d. CYP1A2

c. CYP3A4

CYP450 induction typically leads to:

a. Decreased enzyme biosynthesis

b. Increased drug elimination and reduced plasma levels

c. Decreased detoxification of drugs

d. Drug accumulation and toxicity

b. Increased drug elimination and reduced plasma levels

Grapefruit juice is a well-known example of:

a. Enzyme inducer

b. CYP3A4 inhibitor

c. CYP2C9 inducer

d. CYP450 substrate

b. CYP3A4 inhibitor

T/F: Lipophilic drugs are more likely to be reabsorbed during renal filtration.

True

T/F: Phase II metabolism can occur without Phase I metabolism.

True

T/F: CYP450 enzymes have high substrate specificity.

False

• CYP450 has low substrate specificity

T/F: Enzyme induction can lead to faster metabolism and potential treatment failure.

True

T/F: Aromatic hydroxylation usually occurs at the meta position when the ring has strong electron-donating groups.

False

• Strong electron-donating groups prefer ortho and para hydroxylation

T/F: Halogen substituents on an aromatic ring act as weak deactivators, but still undergo o- and p- hydroxylation.

True

T/F: NADPH-cytochrome P450 reductase transfers electrons to ferric CYP450.

True

Explain drug biotransformation.

Enzymatic chemical modifications that convert lipophilic drugs into more hydrophilic metabolites to facilitate excretion and terminate pharmacological activity.

Differentiate between Phase I and Phase II metabolism.

Phase I: Introduces or exposes functional groups (e.g., oxidation, reduction, etc.)

• Ex: Aliphatic hydroxylation of cyclohexane → cyclohexanol

Phase II: Conjugates drug with endogenous molecules

• Example: Glucuronidation of morphine

Explain the mechanism of action of CYP450 enzymes, including the role of NADPH and the reductase enzyme.

CYP450 enzymes use electrons from NADPH via cytochrome P450 reductase to reduce and activate oxygen, inserting one atom into the substrate (hydroxylation) and forming water from the other.

What is enzyme induction?

Increased CYP enzyme synthesis after exposure to certain drugs or chemicals

How can enzyme induction affect drug-drug interactions?

enhanced metabolism → reduced plasma concentration → possible therapeutic failure

Explain the effect of electron-donating and electron-withdrawing groups on aromatic hydroxylation.

Provide an example of each and indicate which position (ortho, meta, para) is preferred.

Electron-donating groups (EDGs): such as -OH or -NH₂; activates the aromatic ring, favoring ortho/para hydroxylation.

Electron-withdrawing groups (EWGs): such as -COOH or -CN; deactivates the aromatic ring, favoring meta hydroxylation.

Which of the following is true regarding the main goal of drug biotransformation?

a. Increase lipophilicity of the drug

b. Increase kidney reabsorption

c. Increase water solubility for excretion

d. Increase drug half-life

c. Increase water solubility for excretion

Which of the following decreases the rate of metabolism, increasing a drug’s half-life?

a. CYP induction

b. CYP inhibition

c. Enzyme activation

d. Increased renal clearance

b. CYP inhibition

The CYP450 enzyme family contains:

a. Iron-free proteins located in the cytoplasm

b. Hemeproteins that absorb light near 450 nm

c. Transport proteins in the plasma membrane

d. Non-heme flavoproteins in the mitochondria

b. Hemeproteins that absorb light near 450 nm

Which of the following is the most common type of phase I metabolism?

a. Reduction

b. Hydrolysis

c. Oxidation

d. Conjugation

c. Oxidation

Aromatic hydroxylation proceeds via the formation of which of the following?

a. Epoxide (arene oxide)

b. Carbocation

c. Ketone

d. Quinone

a. Epoxide (arene oxide)

A benzene ring containing a -NH₂ substituent is most likely going to undergo hydroxylation at which positions?

a. Meta only

b. Ortho and para

c. Para only

d. None — NH₂ blocks oxidation

b. Ortho and para

A benzene ring with a -COOH substituent undergoes hydroxylation predominantly at which position?

a. Ortho

b. Meta

c. Para

d. Ortho and para

b. Meta

In aliphatic hydroxylation, benzylic carbons are oxidized because they are:

a. Electron-poor

b. Adjacent to an aromatic ring and relatively stable as radicals

c. Terminal carbons of the chain

d. Inaccessible to CYP enzymes

b. Adjacent to an aromatic ring and relatively stable as radicals

ω (omega) hydroxylation refers to oxidation at:

a. The carbon adjacent to the aromatic ring

b. The carbon next to the heteroatom

c. The terminal carbon of an aliphatic chain

d. The carbon adjacent to a carbonyl group

c. The terminal carbon of an aliphatic chain

Which statement is true regarding aromatic substituents and hydroxylation?

a. Strong activators favor meta hydroxylation

b. Strong deactivators favor ortho hydroxylation

c. Weak activators favor ortho and para hydroxylation

d. Weak deactivators completely block hydroxylation

c. Weak activators favor ortho and para hydroxylation

T/F: CYP450 enzymes can oxidize carbon–nitrogen, carbon–oxygen, and carbon–sulfur bonds.

True

T/F: CYP induction increases enzyme biosynthesis and enhances drug clearance.

True

T/F: Aromatic hydroxylation of benzene produces phenol.

True

T/F: Electron-withdrawing groups (EWD) promote ortho and para hydroxylation.

False

• EWDs direct meta, not ortho/para hydroxylation

T/F: Aliphatic hydrocarbons are stable and undergo metabolism only through hydroxylation.

True

T/F: Omega oxidation occurs at the carbon adjacent to a functional group.

False

• Omega oxidation = terminal carbon; omega-1 = adjacent

T/F: Activating groups “beat” deactivating groups in determining hydroxylation position.

True

Explain the chemical difference between oxidation and reduction.

Oxidation: Loss of electrons or gain of oxygen

• Example: Fe²⁺ → Fe³⁺

Reduction: Gain of electrons or loss of oxygen

Describe the process of aromatic hydroxylation catalyzed by CYP450, including the intermediate formed.

Aromatic hydroxylation involves CYP450 forming a highly reactive arene oxide intermediate, which rearranges to yield phenolic metabolites (often para position).

Differentiate between α-hydroxylation and ω-hydroxylation in aliphatic metabolism.

α-hydroxylation: oxidation at carbon adjacent to a functional group or aromatic ring; ω-hydroxylation: oxidation at the terminal carbon of an aliphatic chain.

How do electron-donating and electron-withdrawing groups influence the position of hydroxylation on an aromatic ring?

EDGs (e.g., –OH, –NH₂) activate the ring and favor ortho/para hydroxylation; EWGs (e.g., –COOH, –CN) deactivate and favor meta hydroxylation.

What is the consequence of CYP inhibition on plasma drug concentration and half-life?

CYP inhibition reduces metabolic clearance → increases plasma concentration → prolongs half-life → increases toxicity risk.

Predict the preferred hydroxylation position on an aromatic ring substituted with:

a) -CH₃

b) -COOH

c) -OH

a) -CH₃ → ortho/para (weak activator)

b) -COOH → meta (electron-withdrawing)

c) -OH → ortho/para (strong activator)

If a ring contains both an activator (–OCH₃) and a deactivator (–NO₂), which substituent determines hydroxylation position?

a. Deactivator

b. Activator

c. Both equally

d. None — the ring will not hydroxylate

b. Activator

Aliphatic hydroxylation is most likely to occur at which carbon position?

a. A benzylic or allylic carbon

b. A tertiary aromatic carbon

c. A carbonyl carbon

d. An amide nitrogen

a. A benzylic or allylic carbon

Oxidative deamination occurs mainly with:

a. Tertiary amines

b. Primary or secondary amines

c. Amides

d. Carboxylic acids

b. Primary or secondary amines

During oxidative deamination, the α-carbon hydrogen is oxidized to form a:

a. Carbinolamine intermediate

b. Hydroxylamine intermediate

c. Oxime intermediate

d. Carboxylate

a. Carbinolamine intermediate

Oxidative N-dealkylation of a tertiary amine produces:

a. A secondary amine

b. A primary amine

c. A nitroso compound

d. A carbinolamine

a. A secondary amine

The enzyme families primarily responsible for N-oxidation are:

a. CYP450 only

b. Flavin monooxygenases (FMO) only

c. CYP450 and FMO

d. Dehydrogenases

c. CYP450 and FMO

N-oxidation of a primary amine forms which of the following?

a. Oxime

b. Hydroxylamine

c. N-oxide

d. Carbinol

b. Hydroxylamine

Difference between aromatic and aliphatic hydroxylation

• Aromatic: Hydroxylation on benzene rings; directed by substituent (EDG = ortho/para, EWG = meta)

  • Catalyzed by CYP450

• Aliphatic: Occurs on benzylic, allylic, ω, or ω–1 carbons; increases polarity

  • Catalyzed by CYP450

Describe oxidative deamination

• the functional group affected

• the intermediate formed

• the final products

• Occurs in primary and secondary amines

• The α-C–H oxidized → carbinolamine → decomposes to aldehyde (or ketone) + amine leaves.

• Enzyme: CYP450

Oxidative N-dealkylation - what determines whether the reaction occurs, and what are the typical products?

• In secondary and tertiary amines

• Requires α-C–H next to N

• Forms carbinolamine intermediate → smaller amine + aldehyde/ketone

Describe N-oxidation in terms of:

• which nitrogen types are affected

• which enzyme systems catalyze it

• Direct oxidation of nitrogen atom

• Primary → hydroxylamine; Secondary → oxime; Tertiary → N-oxide

• Enzymes: CYP450 and FMO

What is the major metabolic site on a ‘benzene ring with -CH₃’ (weak activator)?

Ortho/para positions = ↑ electron density

What is the major metabolic site on a ‘benzene ring with -NO₂’ (strong deactivator)?

Meta position = electron withdrawal

What is the major metabolic site on a ‘benzene ring with -Cl’ (weak deactivator)?

Ortho/para positions (exception rule)

Which enzyme system is primarily responsible for oxidative metabolism of most drugs?

a. Alcohol dehydrogenase (ADH)
b. Cytochrome P450 (CYP)
c. Aldehyde dehydrogenase (ALDH)
d. Flavin monooxygenase (FMO)

b. Cytochrome P450 (CYP)

Which statement correctly describes N-oxidation?

a. It occurs only on oxygen atoms

b. It involves oxidation of carbon adjacent to nitrogen

c. It directly oxidizes the nitrogen atom in amines

d. It converts tertiary alcohol into ketones

c. It directly oxidizes the nitrogen atom in amines

Which enzyme can catalyze both S-oxidation and N-oxidation reactions?

a. Cytochrome P450 (CYP)

b. Flavin monooxygenase (FMO)

c. Esterase

d. Aldoketoreductase

b. Flavin monooxygenase (FMO)

Which of the following statements about O-oxidation is true?

a. It is catalyzed primarily by CYP450 only

b. It converts tertiary alcohols to ketones

c. It is catalyzed mainly by alcohol and aldehyde dehydrogenases

d. It produces N-oxides

c. It is catalyzed mainly by alcohol and aldehyde dehydrogenases

• catalyzed mainly by ADH and ALDH

Which statement about S-oxidation is correct?

a. It converts sulfides to sulfoxides and further to sulfones

b. It is catalyzed by esterases

c. It occurs in the cytosol by alcohol dehydrogenase

d. It converts carboxylic acids in alcohols

a. It converts sulfides to sulfoxides and further to sulfones

Which of the following is true about reduction reactions in drug metabolism?

a. They involve adding oxygen to the molecule

b. They are mainly catalyzed by esterases

c. They require NADPH as a cofactor

d. They always deactivate the drug

c. They require NADPH as a cofactor

Which of the following functional groups is most likely to undergo hydrolysis?

a. Amine

b. Ester

c. Alcohol

d. Ketone

b. Ester

Hydrolysis of an amide produces which two products?

a. Alcohol + Acid

b. Alcohol + Aldehyde

c. Carboxylic acid + Amine

d. Amine + Ether

c. Carboxylic acid + Amine

Which statement about flavin monooxygenase (FMO) is false?

a. FMO can catalyze S-oxidation reactions

b. FMOs are microsomal enzymes

c. FMOs are less specific than CYP450s

d. FMO1, FMO2, and FMO3 are the main isoforms involved in drug metabolism

c. FMOs are less specific than CYP450s

• FMOs are more specific than CYPs

List 2 enzymes responsible for oxidative metabolism and specify one reaction each catalyzes.

• CYP450 → Oxidative N-dealkylation

• Alcohol dehydrogenase → Oxidation of primary alcohols to aldehydes

How does hydrolysis of esters differ from hydrolysis of amides in terms of rate and products that are formed?

• Ester hydrolysis — faster; produces acid + alcohol

• Amide hydrolysis — slower; produces acid + amine

What are 3 possible outcomes of phase I metabolism in relation to drug activity?

1. Decreased pharmacological activity (inactivation)

2. Increased activity (activation)

3. Altered activity or toxicity (e.g., reactive metabolites)