Foundations Midterm 2

Question 1

Possible consequences of biotransformation

Answer 1

Increase in activity (toxication), decrease in activity (detoxication), activation, increase in polarity

Question 2

Variables Affecting Drug Metabolism

Answer 2

Age (Infants have low levels of xenobiotics), Gender, Species, Genetic Factors (polymorphisms of drug metabolizing enzymes), Enzyme Induction or Inhibition, Food (grapefruit juice inhibits CYP enzymes), and Disease (decreased liver function with disease)

Question 3

Native Roles of Drug Metabolizing Enzymes

Answer 3

1. Metabolism of non-food materials in the environment (xenobiotics [i.e. low levels of glucuronosyltransferases)
2. Steroid hydroxylation and metabolism
3. Metabolism of centrally acting neurotransmitters
4. Bilirubin conjugation
5. Sulfation of carbohydrates forming mucopolysaccharides

Question 4

Which CYP accounts for the metabolism of more than 50 percent of all drugs?

Answer 4

CYP3A4

Question 5

Primary characteristics of CYP enzymes

Answer 5

1. Contain HEME
2. Utilize NADPH and molecular oxygen
3. Electron transfer VIA NADPH CYP-c reductase (ER)
4. Utilize a radical intermediate

Question 6

During sulfonation, what part of the electrophile stays and what part is left behind?

Answer 6

SO3, or sulfonate is transferred, leaving 3’5’ ADP

Question 7

Aromatic ring hydroxylation typically occurs at which position?

Answer 7

On the para position of a phenol ring

Question 8

What is the cofactor for N-acetylation?

Answer 8

Acetyl Coenzyme A

Question 9

N-Acetyltransferases act on

Answer 9

Aromatic Amines or Hydrazines

Question 10

What does acetylation do to a drug?

Answer 10

Does not increase the hydrophilicity but often inactivates/detoxifies a drug

Question 11

What was the first pro drug?

Answer 11

Prontosil undergoing an azo reduction to form sulfanilamide

Question 12

Why is drug metabolism important?

Answer 12

Biodistribution of drugs - decrease in hydrophobicity and increase in hydrophilicity

Active/toxic metabolites vs Inactive metabolites - the products of phase 1 reactions are more-or-less the parent compounds, but the products of phase 2 are often inactive

Question 13

Describe Omega-1 Aliphatic Hydroxylation

Answer 13

Occurs on non-terminal carbon (CH2) and stops at the secondary alcohol - does not proceed to ketone

Question 14

Where does aromatic ring hydroxylation typically occur?

Answer 14

Para position on phenyl ring

Question 15

What is the result of an aliphatic double bond oxidation?

Answer 15

Diol

Question 16

What happens during oxidative deamination of a Nitrogen within a ring?

Answer 16

Formation of a Lactam by Aldehyde Dehydrogenase which can then undergo further oxidation to a N-oxide

Question 17

What does FMO oxidize?

Answer 17

Mostly Nitrogen and Sulfur, is capable of oxidizing phosphorus and selenium but won’t touch carbon

Question 18

What role does FMO play in metabolism?

Answer 18

Activity increases upon exposure to xenobiotics; performs much more detoxification than biosynthesis

Question 19

FMO oxidation of a primary or secondary amine differs from normal FMO oxidation how?

Answer 19

Primary or secondary amine FMO oxidation goes through a hydroxylamine intermediate

Question 20

What enzyme is responsible for sulfoxide reduction?

Answer 20

Methionine sulfoxide reductase

Question 21

What enzyme is used in glucuronidation?

Answer 21

UDP-Glucuronidetransferase

Question 22

Enzyme used in glycosidation?

Answer 22

UDP-glycosyltransferase

Question 23

Enzyme used in sulfation?

Answer 23

Sulfotransferase

Question 24

Enzyme used in methylation?

Answer 24

Methyltransferase

Question 25

Enzyme used in acetylation?

Answer 25

Acetyltransferase

Question 26

Enzyme used in glutathione conjugation?

Answer 26

Glutathione-S Transferase

Question 27

What does glucuronidation accomplish?

Answer 27

Increase in size makes them readily excreted in bile. Increase in polarity makes them readily excreted in urine.

Question 28

What enzyme can cleave the product of glucuronidation?

Answer 28

Beta Glucuronidase - found within the gut microbiota

Question 29

What nucleophiles exist for glucuronidation?

Answer 29

O, N, S (carbon is rare, must be deprotonated)

Question 30

What cofactor does sulfonation use?

Answer 30

PAPS

Question 31

What is the purpose of sulfonation?

Answer 31

Primarily detoxication

Question 32

Name the hydrolysis enzymes and their corresponding locations

Answer 32

Carboxypeptidase (ER and cytosol); Peptidase (Blood lysosomes)

Question 33

Where does AZO reductase reside? What other enzyme is native to this location?

Answer 33

Microflora of gut; Beta-glucuronidase

Question 34

Name the primary reduction enzymes and where they are found

Answer 34

Carbonyl reductase, disulfide reductase, sulfoxide reductase (cytosol)

Question 35

Name the oxidation enzymes and where they are found

Answer 35

Alcohol dehydrogenase (cytosol) 
Aldehyde dehydrogenase (ER, cytosol)
Monoamine oxidase (cytosol)
Diamine Oxidase (mitochondria)
Cytochrome P450 (ER)
Flavin Monooxygenase (ER)