Pathways of Xenobiotic metabolism -L12 Flashcards Preview

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Flashcards in Pathways of Xenobiotic metabolism -L12 Deck (40)
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What reactions are part of phase 1 metabolism ?

These are all functionalization reactions, making the molecules more reactive
Ideally this metabolism prepares the compound for phase 2 conjugation before excretion


What reactions are part of phase 2 metabolism ?

amino acid conjunction
glutathione conjunction
fatty acid conjunction
These are all conjugative reactions


what is metabolism ?

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


What is the phase 1 pathway sometimes referred to as?

the activation pathway


Where is the microsomal mixed function oxidase system found?

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


What happens in oxidation reactions ?

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


What is the cytochrome p450 reaction ?

NADPH + H+ + 02 + RH goes to NADP+ + h20 + ROH
- the RH has been hydroxylated to ROH so it is more water soluble


What are cytochrome p450 enzymes like ?

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


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

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


What are the main CYP450 families?

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


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

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


What is glutathione-S-transferase?

example of a phase 2 enzyme
causes glutathione conjugation in the liver, kidney, intestine etc


What is glutathione?

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


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

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


What type of molecule is GSH?

an endogenous tripeptide


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

> 20 consisting of 2 subunits


What are GST polymorphisms?

differential distribution between races
5 gene families : 4 cytosolic= alpha, mu, pi and theta and 2 microsomal


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

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


What is an individuals metabolic signature?

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


What can contribute to a "metabolic fingerprint map" ?

genetic factors
- in utero exposure
- lifestyle
- eating habits


What correlation is shown between cyp450 enzymes?

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


What effect can a reduced protein diet have on CYP450s?

reduced CYP3A


What effect can vitamin A and metabolites have on CYP450s?

decreased or increased CYP3A


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

mostly cause reduced drug metabolism


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

increased CYP1A1


What effect can indole from brassicas have on CYP450s?

increased CYP1A2 or increased glucuronidation


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

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


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

decreased p450s


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

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


What is aflatoxin?

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