Phase I and II enzymes Flashcards
Phase I enzymes
Adds OH, does an oxidation
Cytochrome P450 Superfamily
Smooth ER in liver cells (hepatocytes)
single non-selective enzymes
> 27000 P450 sequences
in many tissues
Requires NADPH
Polymorphic distribution (Extensive Metabilism, intermediate metabolism, poor and ultra rapid)
Impact of Ke on bioavailability
Inhibition of metabilic enzymes (higher bio)
Inducers (lower bio)
PM ( Higher bio)
ULR (lower bio)
Nomenclature
Gene and allele
CYP1
Induced by PAH
Activate carcinogens
Includes CYP1 A
and CYP1 A2
CYP1A
Substrate: PAH, Caffeine
Inducers: PAH, dioxins
CYP1A2
Substrate: Acetominophen, caffein
Genotype: Polymorphisms are rare
Inducers: Brassica (brocoli fam), metabolites, charcoal grilled meats
Inhibited: Carrot fam: apiaceous
CYP2 Family
Largest fam in humans
Can Hydoxylate steroids
Sex-specific expressed
Includes
B6, C9 and D6
CYP2B6
Substrates: nicotine
Inhibitor: phenobarbital-type compounds
Expressed: liver, heart
Many different routes of metabolism
CYP2C9
Substrates: Warfin
Genotype: liver, inestin
INDUCIBLE
2 conformations, dangerous to be a slow metaboliser
CYP2D6
Substrate: SSRI
Genotype: liver, brain, heart
NON INDUCIBLE
Can inhibit itself
CYP3 Family
CYP3A4 most abundant enzyme to metabolis drugs
Highly conserved but high inter-individual variability
Motly in liver but also intestin
Epoxide Hydrates (hydrolases)
Epoxide is hydrolysed to make it more polar
ADH
more then 6 genes contributing to 5 classes of dimeric ADH enxymes
ethanol to acetaldehyde by ADH
ALDH
19 ALDJ genes
acethaldehyde to acetic acid by ALDH
acloohol flush reaction
AChE
Reaction: Ester cleavage
Inhibitor: organophospharus xenobiotic
Target of alzeimers pharmacotherapy
FMO
NOT Easily inducudes and inhibited
Different tissues and species acts different
MAO
SubstrateL Monoamide neurotransmitter
Breaks down dopamine and trytptamine
Genotype: 2 types
1) MAO-A: in liver
2) MAO-B: mostly in blood palets
Ayahuasca (yagé): is a plant mixture and a good exemple of how different xenobiotics affect each other
Phase II enzymes
Generally less active then parent but not alwasys
Glutathione S-transferase M1
A glutathinone S-transferase group is TRANSFERED to xenobiotic making it more buly and polar
N-Acetyltransferases (NAT)
Reaction product is more HYDROphobic. Catalyses the transfer of acetyl group from acetyl-coa
COMT
Reaction: O-methylation of cathecholamines
Substrates: L-dopa and methyldopa
- A cytoplasmic form is predominly expressed in liver, intestine and kidney
- A membrane form is expressed in CNS
Thiol methyltransferase
Reaction: S-methylation of aliphatic sulfhydryls
(membrane bound enzyme)
Substrates: xenobiotics thiols
Thiopurine methyltransferase
Reaction: S-methyltransferase of aromatic and heterocyclic sulfhydryls (cytolasmic)
Substrates: xenobiotic thiopurines
