Genetics of non-CYP phase 1 metabolism

Question 1

What are the key polymorphisms in non-P450 phase 1 metabolism?

Answer 1

FMO3, Paraoxonase 1, Cholinesterase and other esterases, Dihydropyrimidine dehydrogenase, Aldehyde dehydrogenase 2

Question 2

What is the role of flavin-linked monooxygenases?

Answer 2

Microsomal enzymes with FAD as prosthetic group, important in oxidation reactions at nitrogen, sulphur and phosphorous centres

Question 3

What is the major hepatic isoform of FMO in humans?

Answer 3

FMO3

Question 4

What compound accumulates in individuals with FMO3 deficiency?

Answer 4

Trimethylamine (TMA)

Question 5

What syndrome is caused by the inability to convert TMA to TMAO?

Answer 5

Fish odour syndrome

Question 6

What is the most common mutation associated with fish odour syndrome?

Answer 6

Pro153Leu

Question 7

What are the common polymorphisms in FMO3?

Answer 7

E158K/E308G compound polymorphism

Question 8

What is the effect of the E158K polymorphism?

Answer 8

Glutamic acid to lysine

Question 9

What is the significance of sulindac in relation to FMO3?

Answer 9

NSAID used in chemoprevention of colon cancer; better outcome with polymorphism due to slower metabolism

Question 10

What are the main types of esterases mentioned?

Answer 10

• Arylesterases
• Butrylcholinesterase
• Carboxyesterases

Question 11

What is the function of paraoxonase (PON1)?

Answer 11

Hydrolyses organophosphates in liver and serum

Question 12

What is the polymorphism associated with low activity of paraoxon hydrolysis?

Answer 12

Polymorphism at codon 192 with Arg to Gln substitution

Question 13

True or False: Low PON1 activity is associated with increased risk of coronary heart disease (CHD).

Answer 13

True

Question 14

What is the role of cholinesterase?

Answer 14

Hydrolyses the muscle relaxant succinylcholine

Question 15

What is the dibucaine number used for?

Answer 15

Assess butrylcholinesterase activity

Question 16

What is the typical inhibition percentage seen in the general population’s dibucaine number?

Answer 16

Approx. 80%

Question 17

What are the genotypic forms of cholinesterase deficiency?

Answer 17

• Atypical form
• Fluoride-sensitive forms
• Silent forms
• Other forms

Question 18

What is the consequence of cholinesterase deficiency?

Answer 18

Prolonged ventilation after use of succinylcholine

Question 19

What is the main role of carboxylesterases?

Answer 19

Metabolism of certain drugs

Question 20

What are the two coding region variants of CES1?

Answer 20

• Gly143Glu - low activity
• Asp260ffs - no activity

Question 21

What is Dihydropyrimidine dehydrogenase (DPYD) important for?

Answer 21

Converts uracil and thymine to dihydro metabolites

Question 22

What is a consequence of DPYD deficiency?

Answer 22

Severe 5-FU toxicity

Question 23

What is the main function of aldehyde dehydrogenases?

Answer 23

Conversion of acetyl aldehyde to acetate following ethanol consumption

Question 24

What is the most common variant allele associated with DYPD deficiency?

Answer 24

G to A base change in intron 14

Question 25

What amino acid substitution is associated with ALDH2 deficiency?

Answer 25

Glu487Lys

Question 26

How is ALDH2 deficiency inherited?

Answer 26

Dominant fashion

Question 27

What is the physiological response following ethanol consumption in some individuals?

Answer 27

Flush and suffer nausea ## Footnote This response is due to the accumulation of acetaldehyde in the blood.

Question 28

What genetic mutation is associated with the flushing response after ethanol consumption?

Answer 28

Amino acid substitution in ALDH2 of Glu487Lys ## Footnote This mutation occurs at the C-terminal end of the protein.

Question 29

What effect does the ALDH2 mutation have on protein stability?

Answer 29

May result in unstable protein being produced

Question 30

What is the inheritance pattern of the ALDH2 mutation?

Answer 30

Dominant fashion ## Footnote Heterozygous and homozygous mutants suffer the 'flushing response'.

Question 31

Why is the inheritance of the ALDH2 mutation considered dominant?

Answer 31

Due to active enzyme consisting of 4 identical subunits

Question 32

What happens when a protein contains just a single ALDH2*2 subunit?

Answer 32

Catalytically inactive

Question 33

What was observed in a small population study regarding flushers and non-flushers?

Answer 33

WT isn't represented ## Footnote WT shows people who flush with alcohol and five people who don't.

Question 34

How many faulty copies of the ALDH2 enzyme are needed to elicit a flushing response?

Answer 34

Only one faulty copy

Question 35

What impact does H2 deficiency have on social drinking habits?

Answer 35

Much less likely to drink socially ## Footnote Specifically noted in individuals with 83 failed H2 deficiency.

Question 36

What percentage of normal controls have failed H2 deficiency?

Answer 36

41% ## Footnote In contrast, alcoholics show only 2.3% H2 deficiency.

Question 37

What correlation was found between alcoholics and liver disease?

Answer 37

Alcoholics with liver disease were found to have lower representation of H2 deficiency

Question 38

How does DHT deficiency relate to individuals with mental health issues?

Answer 38

Similar to the normal population ## Footnote This includes conditions like schizophrenia or drug dependency.

Question 39

What effect does having a DHT deficiency have on social habits?

Answer 39

Greatly impacts social habits