Lecture 7 Flashcards
Microsomal Mixed Function Oxidases (MFOs)
enzymes that are responsible for the incorporation of oxygen into drug molecules (hydroxylation) or oxidative removal of part of a drug molecule (deamination, dealkylation)
Microsomes
Material obtained for in vitro testing after cell homogenization and fractionation of ER
Rough Microsomes are primarily associated with?
protein synthesis
Smooth Microsomes contains what?
oxidative enzymes (MFOs)
Requirements for MFOs or mono-oxygenases
-enzymes require a reducing agent (NADPH) and molecular oxygen (O2)
-MFOs insert only one atom of oxygen into the substrate, and the other oxygen atom becomes part water
-MFOs activate O2, which in turn oxidizes the drug molecule
know this slide
P-450 reductase reduces what?
P-450 drug complex
NADPH does what?
reduce or activate P-450 reductase and reduce/activate molecular oxygen
P-450 oxidizes what?
Oxidizes our drug
Apo
inactive form, contains no heme
Holo
active, has heme
Primary alcohol can get oxidized to 3 metabolites
the -OH, then to an aldehyde, then to a carboxylic acid
Secondary alcohol can get oxidized to 2 metabolites
the -OH, then to a ketone
T/F: Tertiary alcohols can get oxidized
FALSE
No further oxidation!!!!
w-oxidation
oxidation at the terminal methyl group of an aliphatic chain is called an “w-oxidation” (omega position)
w-1
oxidation
oxidation at the secondary to last carbon
Oxidative Dealkylations
primary, secondary, tertiary
smaller the alkyl group, more likely it is to go dealkylation
Oxidative Deamination
occurs in primary and secondary amines
you lose an amine group in the process
the key intermediate is an imine
N-hydroxylation (N-oxidation)
-Primary & Secondary amine yields a hydroxylamine (relatively basic)
-Tertiary Amine yields N-oxide (neutral)
Oxidation of thioethers
-formation of racemic sulfoxide, and eventually sulfone
Oxidative O-dealkylation
-Ether functional group are converted to alcohol
(R-O-R —–> R-OH)
-Most common in aryl-ethers
-basically its the hydroxylation of the alpha C-H bond
Oxidative S- dealkylations
similar to O-dealkylation
Oxidative Desulfurization
-thiocarbonyls, thiophosphates
-conversion of X=S into X=O bond
*in the case of thiophosphates, metabolism yields more reactive phosphate donor
Oxidation of Olefins
-olefins yield an epoxide via oxidation
-alkenes with a C=C
*EPOXIDES ARE ELECTROPHILIC (VERY REACTIVE) AND COULD REACT WITH BIOLOGICAL NUCLEOPHILES VIA ALKYLATION REACTION
Oxidation of allylic/benzylic carbon
-These are electronically activated carbon atoms
-More reactive than a normal aliphatic -C-H bond
Hydroxylation of aromatic ring systems
-aromatic hydroxylation proceeds via an epoxide intermediate, which rearranges to the arenol product
-occurs at the para (4th) position mostly
FATE OF ARENE OXIDE # 1
Rearrange to phenol
-Bioinactivation, Detoxification
FATE OF ARENE OXIDE # 2
Reaction with macromolecules
-if you see a protein just know it has to do with this fate
-Bioactivation ( toxic pathway)
FATE OF ARENE OXIDE # 3
Reaction with Glutathione (GSH)
-highly electrophilic
-enzyme: glutathione S-transferase
-detoxification
FATE OF ARENE OXIDE # 4
Reaction with water
-enzyme: epoxide hydratase (hydrolase)
-detoxification
