Lecture 8 Flashcards
Monoamine Oxidases (MAO)
-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
Oxidation Reactions Catalyzed by other enzymes
From this slide basically know that:
FADH2 + NADPH are the 2 main co-factors involved in flavin monooxygenase system
Phase 1 Metabolism- Reduction
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
what happens in a aromatic nitro group reduction
the nitro is reduced to an amine
what is the reducing agent in aromatic nitro group reduction?
nitro reductase and reductases (they’re enzymes)
what 2 intermediates are formed during Nitro to amino group?
nitroso and hydroxylamine
Overall process of the Nitro to amino group reduction
what happens in an Azo group reduction?
the azo group is reduced to primary amines via hydrazo intermediate
*azo group: N=N
which enzyme is used in azo group reduction
azoreductases
Aldehydes are reduced to _____ alcohols; Ketones are reduced to _______ alcohols
primary, secondary
what is the reducing agents for aldehydes and ketones
aldo-keto reductases and oxidoreductases
what is the key intermediate for azo group reduction?
hydrazo intermediate
overall process of azo group reduction
esters are hydrolyzed by what?
esterases
amides are hydrolyzed by what?
amidases
T/F: Ester hydrolysis is always faster than amide hydrolysis
Dis bish tru
Ester hydrolysis gives off what 2 metabolites?
Alcohol and Carboxylic Acid
Amide hydrolysis gives off what two metabolites?
Amine & Carboxylic acid
Rate of hydrolysis (in order from most to least)
1) Lactone
2) Non-cyclic ester
3) Lactam
4) Non-Cyclic amide
what are the 3 criteria needed for an iminoquinone to form?
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
What is a Phase 2 metabolism?
it involves conjugation of an endogenous substance to a drug or its phase 1 metabolite?
what does a phase 2 metabolism form?
it forms a highly polar, water soluble product that can be excreted
activated piece is a
co-enzyme
Glucoronic acid conjugation
-water solubility is greatly increased ( presence of a carboxylate group and 3 hydroxyl groups)
O-glucoronidation
-alcohol forms an ether group
-carboxylic acid forms an ester group
what is the co enzyme in O-glucoronidation?
UDPGA (UDP-glucoronate)
What is the enzyme in O-glucoronidation?
UGT (glucoronyl transferase)
N-Glucuronidation
-ONLY primary and secondary amines
-Co-enzyme: UDPGA
-Enzyme: UGT
S-Glucorodination
-works if there’s a -S or -SH
C-glucuronidation
-Drugs with highly acidic proton could form C-glucoronic acid conjugates
-Co-enzyme: UDPGA
-Enzyme: UGT
Sulfate Conjugation
Mostly phenols and catechols are modified
PHENOLS GET CONJUGATED AT THE #RD CARBON CONTAINING A -OH
what is the co-enzyme for Sulfate Conjugation?
3’-phosphoadenosine-5’-phosphosulfate (PAPS)
what is the enzyme for sulfate conjugation?
sulfotransferase
Acetylation
GENERAL PURPOSE IS TO TERMINATE BIOACTIVITY/TOXICITY
-important route for modifying drugs that contain amino, sulfonamide, hydrazine, and hydrazide groups
what is the co-enzyme for acetylation? enzyme?
-co-enzyme (Acetyl-CoA)
-Enzyme: Acetyltransferase( transacetylase)
Amino Acid Conjugation
-enzyme: N-acyltransferase
-substrates: carboxylic acids (activated as acyl-CoA)
Amino Acid Conjugation w/ carboxylic acid
Amino Acid Conjugation w/ amines
Methylation
-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
what is the enzyme & co-enzyme for methylation
-co-enzyme: SAM (S-adenosylmethionine)
-Enzyme: methyltransferase
*if there’s a catechol, then it’s COMT
* if there’s a phenol, then its PNMT
Glutathione Conjugation
-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
what are the 3 enzymes involved in Glutathione Conjugation?
-– γ-glutamyltranspeptidase
– Cysteinylglycinase
– N-acetylase
