Genetics of non-CYP phase 1 metabolism Flashcards
What are the key polymorphisms in non-P450 phase 1 metabolism?
FMO3, Paraoxonase 1, Cholinesterase and other esterases, Dihydropyrimidine dehydrogenase, Aldehyde dehydrogenase 2
What is the role of flavin-linked monooxygenases?
Microsomal enzymes with FAD as prosthetic group, important in oxidation reactions at nitrogen, sulphur and phosphorous centres
What is the major hepatic isoform of FMO in humans?
FMO3
What compound accumulates in individuals with FMO3 deficiency?
Trimethylamine (TMA)
What syndrome is caused by the inability to convert TMA to TMAO?
Fish odour syndrome
What is the most common mutation associated with fish odour syndrome?
Pro153Leu
What are the common polymorphisms in FMO3?
E158K/E308G compound polymorphism
What is the effect of the E158K polymorphism?
Glutamic acid to lysine
What is the significance of sulindac in relation to FMO3?
NSAID used in chemoprevention of colon cancer; better outcome with polymorphism due to slower metabolism
What are the main types of esterases mentioned?
- Arylesterases
- Butrylcholinesterase
- Carboxyesterases
What is the function of paraoxonase (PON1)?
Hydrolyses organophosphates in liver and serum
What is the polymorphism associated with low activity of paraoxon hydrolysis?
Polymorphism at codon 192 with Arg to Gln substitution
True or False: Low PON1 activity is associated with increased risk of coronary heart disease (CHD).
True
What is the role of cholinesterase?
Hydrolyses the muscle relaxant succinylcholine
What is the dibucaine number used for?
Assess butrylcholinesterase activity
What is the typical inhibition percentage seen in the general population’s dibucaine number?
Approx. 80%
What are the genotypic forms of cholinesterase deficiency?
- Atypical form
- Fluoride-sensitive forms
- Silent forms
- Other forms
What is the consequence of cholinesterase deficiency?
Prolonged ventilation after use of succinylcholine
What is the main role of carboxylesterases?
Metabolism of certain drugs
What are the two coding region variants of CES1?
- Gly143Glu - low activity
- Asp260ffs - no activity
What is Dihydropyrimidine dehydrogenase (DPYD) important for?
Converts uracil and thymine to dihydro metabolites
What is a consequence of DPYD deficiency?
Severe 5-FU toxicity
What is the main function of aldehyde dehydrogenases?
Conversion of acetyl aldehyde to acetate following ethanol consumption
What is the most common variant allele associated with DYPD deficiency?
G to A base change in intron 14
What amino acid substitution is associated with ALDH2 deficiency?
Glu487Lys
How is ALDH2 deficiency inherited?
Dominant fashion
What is the physiological response following ethanol consumption in some individuals?
Flush and suffer nausea
This response is due to the accumulation of acetaldehyde in the blood.
What genetic mutation is associated with the flushing response after ethanol consumption?
Amino acid substitution in ALDH2 of Glu487Lys
This mutation occurs at the C-terminal end of the protein.
What effect does the ALDH2 mutation have on protein stability?
May result in unstable protein being produced
What is the inheritance pattern of the ALDH2 mutation?
Dominant fashion
Heterozygous and homozygous mutants suffer the ‘flushing response’.
Why is the inheritance of the ALDH2 mutation considered dominant?
Due to active enzyme consisting of 4 identical subunits
What happens when a protein contains just a single ALDH2*2 subunit?
Catalytically inactive
What was observed in a small population study regarding flushers and non-flushers?
WT isn’t represented
WT shows people who flush with alcohol and five people who don’t.
How many faulty copies of the ALDH2 enzyme are needed to elicit a flushing response?
Only one faulty copy
What impact does H2 deficiency have on social drinking habits?
Much less likely to drink socially
Specifically noted in individuals with 83 failed H2 deficiency.
What percentage of normal controls have failed H2 deficiency?
41%
In contrast, alcoholics show only 2.3% H2 deficiency.
What correlation was found between alcoholics and liver disease?
Alcoholics with liver disease were found to have lower representation of H2 deficiency
How does DHT deficiency relate to individuals with mental health issues?
Similar to the normal population
This includes conditions like schizophrenia or drug dependency.
What effect does having a DHT deficiency have on social habits?
Greatly impacts social habits
