Lecture 8

Question 1

Monoamine Oxidases (MAO)

Answer 1

-catalyze oxidative deamination of endogenous catecholamines
-located in nerve terminals and peripheral tissues
-inhibited by a class of antidepressants called MAO inhibitors
-these drugs can cause severe or fatal drug/drug interactions with drugs that increase release of catecholamines or inhibit their reuptake in nerve terminals

Question 2

Oxidation Reactions Catalyzed by other enzymes

Answer 2

From this slide basically know that:

FADH2 + NADPH are the 2 main co-factors involved in flavin monooxygenase system

Question 3

Phase 1 Metabolism- Reduction

Answer 3

The 3 major types of reduction occurs during drug metabolism are:

1) Nitro to amino group (NO2 —–> NH2)
2) Azo to amino group (N=N —-> NH2 + NH2)
3) Aldehydes and ketones to alcohols

Question 4

what happens in a aromatic nitro group reduction

Answer 4

the nitro is reduced to an amine

Question 5

what is the reducing agent in aromatic nitro group reduction?

Answer 5

nitro reductase and reductases (they’re enzymes)

Question 6

what 2 intermediates are formed during Nitro to amino group?

Answer 6

nitroso and hydroxylamine

Question 7

Overall process of the Nitro to amino group reduction

Answer 7

Question 8

what happens in an Azo group reduction?

Answer 8

the azo group is reduced to primary amines via hydrazo intermediate

*azo group: N=N

Question 9

which enzyme is used in azo group reduction

Answer 9

azoreductases

Question 10

Aldehydes are reduced to _____ alcohols; Ketones are reduced to _______ alcohols

Answer 10

primary, secondary

Question 11

what is the reducing agents for aldehydes and ketones

Answer 11

aldo-keto reductases and oxidoreductases

Question 12

what is the key intermediate for azo group reduction?

Answer 12

hydrazo intermediate

Question 13

overall process of azo group reduction

Answer 13

Question 14

esters are hydrolyzed by what?

Answer 14

esterases

Question 15

amides are hydrolyzed by what?

Answer 15

amidases

Question 16

T/F: Ester hydrolysis is always faster than amide hydrolysis

Answer 16

Dis bish tru

Question 17

Ester hydrolysis gives off what 2 metabolites?

Answer 17

Alcohol and Carboxylic Acid

Question 18

Amide hydrolysis gives off what two metabolites?

Answer 18

Amine & Carboxylic acid

Question 19

Rate of hydrolysis (in order from most to least)

Answer 19

1) Lactone
2) Non-cyclic ester
3) Lactam
4) Non-Cyclic amide

Question 20

what are the 3 criteria needed for an iminoquinone to form?

Answer 20

1) Is there a Benzene ring
2) Is the nitrogen attached to a benzene ring
3) Para to the N, C-H or C-OH

if yes, then you can form an iminoquinone

Question 21

What is a Phase 2 metabolism?

Answer 21

it involves conjugation of an endogenous substance to a drug or its phase 1 metabolite?

Question 22

what does a phase 2 metabolism form?

Answer 22

it forms a highly polar, water soluble product that can be excreted

Question 23

activated piece is a

Answer 23

co-enzyme

Question 24

Glucoronic acid conjugation

Answer 24

-water solubility is greatly increased ( presence of a carboxylate group and 3 hydroxyl groups)

Question 25

O-glucoronidation

Answer 25

-alcohol forms an ether group
-carboxylic acid forms an ester group

Question 26

what is the co enzyme in O-glucoronidation?

Answer 26

UDPGA (UDP-glucoronate)

Question 27

What is the enzyme in O-glucoronidation?

Answer 27

UGT (glucoronyl transferase)

Question 28

N-Glucuronidation

Answer 28

-ONLY primary and secondary amines
-Co-enzyme: UDPGA
-Enzyme: UGT

Question 29

S-Glucorodination

Answer 29

-works if there’s a -S or -SH

Question 30

C-glucuronidation

Answer 30

-Drugs with highly acidic proton could form C-glucoronic acid conjugates
-Co-enzyme: UDPGA
-Enzyme: UGT

Question 31

Sulfate Conjugation

Answer 31

Mostly phenols and catechols are modified
PHENOLS GET CONJUGATED AT THE #RD CARBON CONTAINING A -OH

Question 32

what is the co-enzyme for Sulfate Conjugation?

Answer 32

3’-phosphoadenosine-5’-phosphosulfate (PAPS)

Question 33

what is the enzyme for sulfate conjugation?

Answer 33

sulfotransferase

Question 34

Acetylation

Answer 34

GENERAL PURPOSE IS TO TERMINATE BIOACTIVITY/TOXICITY
-important route for modifying drugs that contain amino, sulfonamide, hydrazine, and hydrazide groups

Question 35

what is the co-enzyme for acetylation? enzyme?

Answer 35

-co-enzyme (Acetyl-CoA)
-Enzyme: Acetyltransferase( transacetylase)

Question 35

Amino Acid Conjugation

Answer 35

-enzyme: N-acyltransferase
-substrates: carboxylic acids (activated as acyl-CoA)

Question 36

Amino Acid Conjugation w/ carboxylic acid

Answer 36

Question 37

Amino Acid Conjugation w/ amines

Answer 37

Question 38

Methylation

Answer 38

-most common substrates are phenols, catechols, and amines
-water solubility of metabolites is not increased unless quaternary ammonium functionality is form, so basically it inactivates & detoxify

Question 39

what is the enzyme & co-enzyme for methylation

Answer 39

-co-enzyme: SAM (S-adenosylmethionine)
-Enzyme: methyltransferase

*if there’s a catechol, then it’s COMT
* if there’s a phenol, then its PNMT

Question 40

Glutathione Conjugation

Answer 40

-this is a detoxification pathway
-metabolites a sulfhydryl group (thiol C-SH)
-thiol groups react with electrophilic substances to form inactive adducts
-GSH can’t be excreted, so it undergoes a series or reactions to form water-soluble mercaptopuric acid derivatives
-there’s no coenzyme

Question 41

what are the 3 enzymes involved in Glutathione Conjugation?

Answer 41

-– γ-glutamyltranspeptidase
– Cysteinylglycinase
– N-acetylase