Phase I Non-CYP Mediated Flashcards
Describe flavin linked monooxygenases
Microsomal enzyme + FAD prosthetic group
Important in oxidation reactions
5 different forms
What is the major FMO hepatic isoform
FMO3
What is TMA
Unpleasant smelling compound
Breakdown product of precursors
Gut bacteria involved in TMA formation
What is the normal metabolism of TMA
TMA -> TMAO by FMO3
TMAO less volatile and loses odour
What causes fish odour syndrome
Lack of FMO3
No TMA -> TMAO
What common mutation is associated with fish odour syndrome
Pro153Leu
Describe the Pro153Leu polymorphism in fish odour syndrome
Compete loss of activity
Functionally significant
No effect of methimazole metabolism
What polymorphism are responsible for fish odour syndrome in children
E158K
E308G
Describe the function of arylesterase- paraoxonase
Hydrolyses organophosphates in the liver and serum
What polymorphisms of paraoxonase cause low activity
PON1
Describe the protective effects of paraoxonase polymorphism
Hydrolyses oxidised LDL-associated cholesterol
Associated with HDL
How does PON1 increase the risk of CHD
Low activity of paraoxonase
No links to polymorphism
How does the Arg192Gln polymorphism in paraoxonase affect activity
Low activity
Amino acid substitution in promoter substitution
What is PXR
CYP3A4 txn regulator
Where are the polymorphisms for PXR found
Upstream and coding sequences
-25000 is ATG start site, close to promoter region
What are the 2 PXR polymorphisms
C -> T
G -> A
Why are the 2 PXR polymorphisms seen together
Linkage disequilibrium
When is there increased gene expression in PXR
When promoter regions contains T over C
Describe CYP1A1
Extra-hepatic
Induced by tobacco smoke or PAHs
Induction mediated by Ah receptor
Where are CYP1A1 polymorphism located
Upstream and ion coding sequence
Describe the Arg554Lys polymorphism in AhR
Presence of variant correlates with high induced CYP1A1 activity
What is the function of butyrylcholinesterase
Plasma esterase i.e high levels in plasma
Hydrolyses succinylcholine
What % of population of is heterozygous for cholinesterases
5%
Associated with poor hydrolysis of compound
How can you detect individuals with deficiency in cholinesterases
Inhibition pattern of benzoylchlone hydrolysis
With either dibucaine or fluoride
Atypical variant shows less inhibition than wild-type
What are the 3 forms of cholinesterase deficiency
Atypical from: abnormal dibucaine inhibiton
Fluoride sensitive: amino acid substitutions
Silent form: frameshift or premature stop codon
What are the 2 polymorphisms of carboxyesterases
CES1 = high levels in liver
CES2 = high levels of extrahepatic tissues
What is the consequence of Gly143Glu in CES1
Low activity
What is the consequence of Asp260Fs in CES1
No activity
Rare
Describe dihydropyrimidine dehydrogenase
Converts U -> T dehydro metabolites
Metabolised by 5-flurouracil
What is the common variant of dihydropyrimidine dehydrogenase
G->A intron 14
= skipping of exon 14
= truncated protein
What genotype variant is toxic in dihydropyrimidine dehydrogenase
Heterozygous
2-3% Europeans
What are the 2 forms of aldehyde dehydrogenase
ALDH1 (cytosolic)
ALDH2 (mitochondrial)
What variant of aldehyde dehydrogenase causes low activity
Glu487Lys in ALDH2
What is the inheritance of Glu487Lys in ALDH2
Dominant inheritance
Heterozygous and homozygous suffer flushing Response
Where is the ALDH2 mutation common
East Asia
