Lecture 10 - Non P450-mediated phase I reactions Flashcards
2 types of non-P450 phase 1 metabolisms
- oxidation
- hydrolysis
what are the 4 non -P450 phase 1 OXIDATION metabolism reactions?
- flavin- linked monooxygenases (FMO)
- prostaglandin H-synthase - dependent co-oxidation
- amine oxidases
- oxidoreducatases
what are the 4 non -P450 phase 1 HYDROLYSIS metabolism reactions?
- esterases
- epoxide hydrolases
what are the Flavin-linked monooxygenases
(FMO)?
- multienzyme fam
- smaller but similar to cyt P450
- requirement for NADPH and O2
- Overlap in substrate specificity with certain P450 enzymes BUT
often yield distinct metabolites
Properties of FMO-properties
- oxidises nucleophilic nitrogen, phosphorous or sulphur centres
- contains FAD as prosthetic group
- located in ER fraction
- 5 dif isoforms sowing 50-55% identity w one another
- not inducible except FMO5 by rifampicin
FMO_ is the only FMO found at high
levels in human liver
3
give the 3 enzymes in oxidation peroxidase reaction
Prostaglandin H-synthase
Myeloperoxidase
Lactoperoxidase
Particularly important in cells which lack other
xenobiotic oxidising enzymes
oxidation mechanism important in extrahepatic tissues
what are the 2 things that prostaglandin H-synthase (pghs) do?
- make prostaglandins
- helps oxidase foreign substances
give an example of PGHS making prostaglandin (2)
COX
- converts arachidonic acid > PGG2
Peroxidase
- converts PGG2 > PGH2
co-oxidation of xenobiotic to metabolite
PGG2- PGH2
How is Prostaglandin H-Synthase (PGHS) Different from P450 & FMO?
P450 ezymes use oxygen and NADPH to add oxygen to drugs
- PGHS does not
example of PGHS doing something bad?
high paracetamol doses can be converted to NAPQI in the kidney
Monoamine oxidase (MAO) is a ________ enzyme which
oxidises by a __-dependent pathway
mitochondrial
FAD
Main role of MAO is in metabolism of _______ but also
_____ some drugs
neurotransmitters
oxidises
Propananol is mainly metabolised by MOA__
a
Use NAD(P) for _____ & NAD(P)H for _____.
oxidation reduction
give examples of oxidoreductases
- alcohol dehydrogenase
- aldehyde dehydrogenase
- carbonyl reductase
- NAD(P)H quinone oxidoreductase
These enzymes are ______ except for one form of aldehyde
dehydrogenase
cytosolic
what is the main enzyme that breaks down alcohol in body ?
alchohol dehydrogenase (ADH)
What does alcohol dehydrogenase need to work?
NAD+
converts alcohol to carbonyls
Carbonyl Reductase function of action
- enzyme adds or removes oxygen in cirtain chemicals
- uses NADP+/NADPH to help with the reaction
- changes carbonyl compounds into alcohols and vice versa
what does carbonyl reductase break down?
- quinones
- prostaglandins
- menadione
- drugs and toxins
what does NAD(P)H reduce quinones to?
hydroquinones
(without semiquinone as an intermediate )
- protects cells from toxic and oxidative damage
difference between two-electron vs single electron reduction of quinones ?
two>
Quinone - hydroquinone
no harmful ROS
safe detoxification - protects cells from toxins
single>
quinone - semiquinone
Generates ROS
can be harmful cause oxidative stress and damage
where are esterases found?
- plasma
- liver
cytosolic & microsomal forms
what metabolises ASPIRIN?
butyrylcholinesterase
what metabolises COCAIN and HEROIN?
Carboxylesterase 1
what metabolises PROCAINE?
carboxylesterase 2
function of CARBOXYLESTERASES
Catalyse the hydrolysis of wide range of chemicals
- CE1 prefers substrate with a ____ alcohol group, ____ acyl group
small
large
CE2 prefers substrate with a _____ alcohol group, ___ acyl group
large
small
what does butyrylcholineesterase do?
major contributor to hydrolysis of aspirin to salicylate in plasma
what are epoxide hydrolases (EPH) ?
specialised type of esterase that in presence of water cleaves epoxides
what is Paroxonase (PON) 1 ?
multifunctional enzyme with arylesterase lactonase and paroxonase activities
where is PON made?
liver also found in plasma
what does PON do?
- role of degration of oxidise lipids
