Non Cyp Phase 1 Flashcards
What enzymes cause oxidation reactions
Flavin linked monooxygenases (FMO)
Prostaglandin H synthase dependent co oxidation
Amine oxidase
Oxidoreductase
What enzymes cause hydrolysis
Esterases
Epoxide hydrolases
Where are FMOs found
ER
What do FMOs oxidise
Nucleophilic N, P or S centres
What does FMO require
NADPH, O2 and FAD prosthetic group
FMO reaction mechanism
- NADPH reduces FAD —> FADH2
- O2 binds NAPD+-FADH2 complex
- Forms FADH-OOH
- Reacts with nucleophile substrate
- One O is incorporated into substrate and the other into water
- H2O and NADP+ is released
How many isoforms of FMO is there
5 - show 50-55% identity with each other
Give 2 examples of FMO catalysed reactions
N-deacetyl ketaconozole —> N-deacetyl-N-hydroxyketaconozole
Tamoxifen —> Tamoxifen-N-oxide
Which FMO is found at high levels in the human liver
FMO3
Which FMO is found in the human kidney
FMO1
Which FMO is found in rat liver
FMO1
Which FMOs are found in rat kidney
FMO1 FMO3 FMO4
Explain the co-oxidation quality of PGHS
COX activity (arachidonic acid —> PGG2)
Peroxidase activity (PGG2 —> PGH2)
What is PGHS’s role in paracetamol overdose
High doses of paracetamol can be converted to the toxic N-acetylquinoneimime in the kidney
What do amine oxidases oxidise
Monoamine
Diamines
Polyamines
What do MAOs
Metabolise neurotransmitters via FAD-dependent pathway
Which MAO metabolises propranolol
MAOA
Where are amine oxidases found
Mitochondria
Describe metabolism of dopamine
DA -MOA-> X -ald dehydrogenase-> HVA
4 oxidoreductases
Alcohol dehydrogenase
Aldehyde dehydrogenase
Carbonyl reductase
NAD(P)H quinone oxidoreductase
What are oxidoreductases dependent on
NADP in the oxidising direction
NADPH in the reducing direction
Where are oxidoreductases found
Cytosol
What is the “normal” method of ethanol detoxification
Alcohol dehydrogenase
(CYP2E1 used excess ethanol as a substrate)
Ethanol metabolism pathway
Ethanol -ADH-> acetaldehyde -AlDH-> carboxylic acid
What plays a role in cyclophosphamide metabolism
Aldehyde dehydrogenase
GSTs
Alcohol dehydrogenase
CYP2C9
CYP3A4
What do carbonyl reductases do
Reduces quinones, prostaglandins, menadione
Specific substrate of carbonyl reductase
Doxorubicin to doxorubicinol
Why are quinone oxidoreductases important
Reduce quinones directly to hydroquinones without semiquinone intermediate by using 2 electrons instead of 1
- avoids generation of singlet oxygen
Where are esterases found
Plasma and liver
Cytosolic and microsomal forms
4 types of esterase
Butyrylcholinesterase
Carboxylesterase 1
Carboxylesterase 2
Paraoxonase
What does cholinesterase metabolise
Aspirin
What does CES1 metabolise
Cocaine / heroin
What does CES2 metabolise
Procaine
What does paraoxonase metabolise
Statins
What do CES1 and CES2 prefer
CES1 - small OH group, large acyl group
CES2 - larger OH group, small acyl group
What do epoxide hydrolases do
Cleave epoxides in the presence of water
Where are EPHs found
Cytosol and microsomes
Epoxide hydrolase in benzoapyrene genotoxicity
BaP —(CYP1)—> B-epoxide —(EPH)—> B-diol —(CYP1)—> BPDE
What does PON1 do
Protects LDL and HDL from lipid peroxidation
