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Food & Cancer 3340 > Pathways of Xenobiotic metabolism -L12 > Flashcards

Pathways of Xenobiotic metabolism -L12 Flashcards

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1
Q

What reactions are part of phase 1 metabolism ?

A 
oxidation 
reduction 
hydrolysis
hydration 
dethioacetylation 
isomerisation 
These are all functionalization reactions, making the molecules more reactive 
Ideally this metabolism prepares the compound for phase 2 conjugation before excretion
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2
Q

What reactions are part of phase 2 metabolism ?

A 
glucuronidation 
sulfation 
methylation 
acetylation 
amino acid conjunction 
glutathione conjunction 
fatty acid conjunction 
condensation 
These are all conjugative reactions
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3
Q

what is metabolism ?

A

making a substance more water soluble so they are excreted more rapidly
the 2 phases of metabolism dont always necessarily go in order - if chemicals come into contact with enzymes at the right time and in the right conditions then they will react

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4
Q

What is the phase 1 pathway sometimes referred to as?

A

the activation pathway

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5
Q

Where is the microsomal mixed function oxidase system found?

A

it is cytochrome p450 dependent and it is present notably within the endoplasmic reticulum of cells within the liver, kidney, lung and intestine

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6
Q

What happens in oxidation reactions ?

A

initial insertion of oxygen followed by rearrangement and/or decomposition to final products
- this is the most important route due to diversity and importance of reactions catalysed-cytochrome p450 system - it metabolises lots of different small molecules

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7
Q

What is the cytochrome p450 reaction ?

A

NADPH + H+ + 02 + RH goes to NADP+ + h20 + ROH

- the RH has been hydroxylated to ROH so it is more water soluble

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8
Q

What are cytochrome p450 enzymes like ?

A

MWt between 45000-55000
haem containing enzymes
family of closely related isoforms in the ER membrane
>50 human cyp450 identified

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9
Q

What cytochrome p450 enzyme is the most prominent in the liver ?

A

CYP3As quantitatively the major sub-family in human livers - expressed in 30% of total
-CYP3A4 shows considerable inter-individual variation - 1 to 2 orders of magnitude (big difference between individuals), these differences are genetic variation but induction of the enzymes is possible

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10
Q

What are the main CYP450 families?

A 
CYP1= 1a2
CYP2= 2d6, 2c19, 2e1
CYP3= 3a
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11
Q

What are the difference extents of clearance variability between cyp450 enzymes?

A 
1A= about 40 fold 
2C= 25-100 fold 
2D6= >1000 fold
2E1= about 20 fold 
3A4= about 20 fold 
large differences between individuals for the clearance of drugs and metabolites
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12
Q

What is glutathione-S-transferase?

A

example of a phase 2 enzyme

causes glutathione conjugation in the liver, kidney, intestine etc

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13
Q

What is glutathione?

A

its an important protective compound leading to detoxification of many electrophilic xenobiotics
R-CH2-X detoxified by GSH to R-CH2-SG

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14
Q

What characteristic about glutathione-S-transferases is similar to CYP450s?

A

They also demonstrate inter-individual variation

higher levels of these enzymes may help people remove toxic compounds more easily than those who have lower levels

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15
Q

What type of molecule is GSH?

A

an endogenous tripeptide

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16
Q

How many different isoforms of glutathione-S-transferase are there in man ?

A

> 20 consisting of 2 subunits

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17
Q

What are GST polymorphisms?

A

differential distribution between races

5 gene families : 4 cytosolic= alpha, mu, pi and theta and 2 microsomal

18
Q

Other than genetic variations how can phase 1 and phase 2 enzymes demonstrate inter-individual variation ?

A

differences can arise because of induced differences in expression levels
the things you eat can affect your metabolism signature
this can affect your health outcome

19
Q

What is an individuals metabolic signature?

A

an individuals exposure to food and environmental compounds leaves a metabolic signature in our body, changing the way we are interacting with our environment

this metabolic signature may serve as a basis for optimising an individuals diet-health relationship

20
Q

What can contribute to a “metabolic fingerprint map” ?

A 
genetic factors 
environmental
- in utero exposure
- lifestyle
-diet
 - eating habits
21
Q

What correlation is shown between cyp450 enzymes?

A

levels of activity between different ones shows correlation
if someone has a large amount of one cyp450 then they are likely to have a lower amount of another but this pattern may be opposite in another individual

22
Q

What effect can a reduced protein diet have on CYP450s?

A

reduced CYP3A

23
Q

What effect can vitamin A and metabolites have on CYP450s?

A

decreased or increased CYP3A

24
Q

What effect can deficiencies in Fe, Ca, Mg, Zn, Cu, Se, I have on CYP450s?

A

mostly cause reduced drug metabolism

25
Q

What effect can a pyrolysis products in your diet have on CYP450s?

A

increased CYP1A1

26
Q

What effect can indole from brassicas have on CYP450s?

A

increased CYP1A2 or increased glucuronidation

27
Q

What effect can grapefruit juice in your diet have on CYP450s?

A

increased CYP1A2, CYP3A4 and CYP2A6
- can have a very strong effect and therefore sometimes people are not allowed to take it if they are taking certain drugs

28
Q

What effect can flavanoids, diallyl sulphide (garlic) and curcumin have on CYP450s?

A

decreased p450s

29
Q

What are phase 1 and 2 enzymes unfortunately unable to do ?

A

cannot tell the difference between beneficial molecules such as vitamins and toxins such as carcinogens

30
Q

What is aflatoxin?

A

mycotoxins that are TOXIC, CARCINOGENIC, MUTAGENIC and TERATOGENIC -particularly to LIVER
- weakly carcinogenic because they can intercalate between the DNA base pairs
its an accepted human carcinogen

31
Q

Why is aflatoxin B1 strongly carcinogenic?

A

because it can be metabolised to the epoxide form which can covalently link directly to DNA -metabolised by phase 1 enzymes
the epoxide is formed by a oxygen molecule forming across the double bond
heptocarcinogenic mycotoxin

32
Q

What are the different aflatoxin molecules ?

A

B1, B2, G1 and G2
B1 and B2 differ by presence of a double bond
Gs differ from Bs due to a 6 helical ring

33
Q

What organisms are aflatoxins particularly dangerous ?

A

poultry and fish but appear to be less damaging to humans

34
Q

Why are there not many directs carcinogens in food?

A

because lots of the food we eat contains DNA

35
Q

What is the critical product of aflatoxin B1?

A

the exo-epoxide

all other products formed from oxidation are at least partially detoxified

36
Q

What is the half life of the exo-epoxide and what does it mean?

A

half life= only 1 second
however
the binding and intercalation with DNA is so efficient that a high yield of DNA adducts is obtained
it is still stable enough to migrate from the ER to the DNA in the nucleus

37
Q

What % of hepatocellular carcinoma is caused by AFB1?

A

about 50% in parts of the world where AFB1 contaminates food - many showing mutations in codon 248 of p53 gene
transversion of G to T in 3rd position of codon

38
Q

Why cant aflatoxin produce aspergillus flavus mold in this country?

A

because the weather isn’t hot enough and humid enough at the same time

39
Q

Why is it important to understand phase1 and phase2 enzymes?

A

because these enzymes might be important in food-related cancer - so understanding them might help us protect ourselves against carcinogens such as aflatoxin

40
Q

Why is the balance between producing the phase 1 epoxide of aflatoxin and the phase 2 producing glutathione conjugate important?

A

it is a complicated relationship because if you wanted to enhance the beneficial phase 2 component then you would need to increase the dangerous phase 1 component

Food & Cancer 3340 (19 decks)

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