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Food Toxicology -TOX30306 > Week 1 - Biotransformation + carcinogens > Flashcards

Week 1 - Biotransformation + carcinogens Flashcards

1
Q

The development of many cancers likely involves more than ____ changes before cancer develops

A

3

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2
Q

why does mutagenicity doesn’t equal carcinogenicity ?

A

this is are the reasons wht the genotoxity doesn’t results in the cancer formation necesarly. so one mutation is not suffecient because you need the activation of the oncogenes and you also need mutations that inactivates the tumor suprressor (which you have two copies so 2 mutations)

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3
Q

T or F : there can be a threshold for the carcinogenicity of a compound

A

true, if the compound is non-genotoxic like in the case of ocumarin, the continuous toxic and dammage of the cells and the proliferation to replace those cells can lead to uncontrolled proliferation. So for the case of the non-genotoxic you could have a threshold if it binds to the receptor only

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4
Q

_____ is a non-genotoxic carcinogen in cinnamon

A

coumarin

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5
Q

T or F : coumarin carcinogenicity is through secondary liver toxicity and so it can be prevented

A

true so preventing the liver toxicity by the NOAEl, you can prevent the cancinoergicity for the humans.

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6
Q

carcinogenicity of estragole and methyleugenol is related to____

A

DNA adduct formation

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7
Q

Can you explain the mechanism by which methyleugenol becomes genotoxic ?

A

In phase 2 : doesn’t lead to the excretion and leads to the introduction of the sulfate groups and this sulfoxi metabolite binds to the DNA and forms adducts

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8
Q

T or F : MOE to be used by risk managers to set priorities

The MOE is nota quantitative risk assessment

A

true

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9
Q

T or F : it is not allowed to add methyleugenol as a pure compound to foods

A

true since the MOE is 116. It is allowed to add botanicals that may contains methyleugenol like basil, other spices and some vegetables since the MOE is 4400 ot 44 000

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10
Q

Estragole and methyleugenol are in the categories of ____ which are considered genotoxic because of ____

A

alkenylbenzene
genotoxic because of DNA adduct formation

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11
Q

What are the three categories of unavoidable carcinogens seen in class

A
  1. Naturally present : Phytoxins, pyrrolizidine alkoids, alkenylbenzen (estragole and methyleugenol), Mycotoxins (aflatoxins)
  2. Endogenously formed : nitroamines
  3. Formed upon food processing (heating)
    PAH, heterocyclic amines, acrylamide
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12
Q

____ are present in various plants and have been found in honey and tea

A

pyrrolizidine alkaloids

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13
Q

pyrrolizidine alkaloids carcinogenicity mode of action is throught

A

formation of DNA adducts

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14
Q

____ is a mycotoxin produced by _____ (mold)

A

aflatoxin B1 produced by the aspergillus flavus mold

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15
Q

What is the mode of action of aflatoxin B1 ?

A

mutation to hotspots for the P53 tumor suppressor gene and so it induces liver cancer.

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16
Q

t or f : Aflatoxin B1 needs biotransformation to be genotoxic

A

true, it is the epoxide of aflatoxin that is genotoxic

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17
Q

T or F : the MOE of Aflatoxin B1 raises concern

A

true since it is at 88-483

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18
Q

T or F : nitrosamine can be created from the combination of nitrite formed from nitrate coming from greens and the amine in fish to form nitroamine a carcinogen

A

true, but vitamin C can inhibit the reaction. The compound formed in NDMA

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19
Q

T or F : nitroamines is a problem for young children

A

true, their MOE is under 10 000

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20
Q

PAH are formed upon ___ reactions while heterocyclic amines and acrylamide are formed by ___ reactions

A

PAH : pyrolysis
Acrylamide and heterocyclic amines : Maillard reactions

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21
Q

Which of the heterocycline amine is the most well known carcinogen ?

A

Phip, also known as the hamburger carcinogen

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22
Q

the lowest BMDL10 for PhIP can give ____ tumors

A

prostate tumors

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23
Q

T or F : heterocyclic amines are high priority

A

false, they have a MOE of 15 000

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24
Q

Acrylamide is a concern in ___ and ___ . Acrylamide is genotoxic because of ___

A

fries and toasted bread
genotoxicity is due to the formation of glycidamide by the CYP enzymes

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25
Q

T or F : neurotoxicity will be seen at lower dose than genotoxicity in the case of acrylamide

A

false, it is the other way around

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26
Q

_____ are found in coffee, canned and jarred foods

A

furans

27
Q

How are furans formed

A

Formed from heating : by thermal degradation from ascorbic acid, amino acids, carbohydrates, unsaturated fatty acids and carotenoids

28
Q

Why is it that the furan MOES might be higher than estimated

A

because methylfurans were not taken into account and the MOE is already at 36-582

29
Q

Are furans a concern ?

A

yes because the MOE is at 36-582

30
Q

What are the supposed mechanisms by which food can be anti-carcinogen

A

Reduction of effects of carcinogens by modulation of biotransformation enzymes
Reduction of inflammation
Reduce oxidative/electrophilic stress
Reducing proliferation tumour cells
Reducing bioavailability

31
Q

How does brocoli reduces the aflatoxin toxicity ?

A

the chlorophyllin present in green vegetable will make comlexes with the aflatoxin and so reduce its bioavailability

32
Q

How does isothocyanates reduces the oxidative stress ?

A

binding of the NRF-2 receptor and activation of a pathway leading to the expression of enzymes (GST) helping with protection against oxidative stress by scaanding reactive DNA aducts

33
Q

What is the step in ADME that explains the interindividual differences

A

The biotransformation

34
Q

EXAM : why is it important to study the biotransformatino in the toxicological studies

A

1- Because the detoxification (and subsequent excretion) of chemicals depends on the biotransformation
2- because biotransformation can lead to the bioactivation

35
Q

What are the two phases of biotransformation ?

A
  • *Phase 1** : modification to make the compound polar
  • *Phase 2** : conjugation to make the compound hydrophilic
36
Q

What are the various reactions that occur in the phase 1 biotransformation ?

A
  1. Oxidation
  2. Reduction
  3. Hydrolysis
37
Q

What are the various reactions that occur in the phase 2 biotransformation ?

A

phase 2 are conjugation reaction to produce an hydrophilic metabolite either by the conjugation of the compound with :

  1. water
  2. Glutathione
  3. Glucuronic acid
  4. Sulfate
  5. Acetate
  6. Amino acid
  7. Methyl groups
38
Q

Why is it important to know the organ in which the biotransformation occurs ?

A

because the compound will be at its most active if the metabolite is reactive in the specific organ it was transformed in

39
Q

CYP is a family of enzyme important in the phase __ of biotransformation

A

1

40
Q

What are the enzymes seen in class important for the phase 2 of biotransformation ?

A

Glucuronosyltransferase : ●UGT
Sulfotransferase : ●SULT
Glutathione S-transferase : ●GST
Epoxide hydrolases : ●EH

41
Q

Why are three reasons explaining the broad substrate specificity ?

A
  1. Various phase I and II iso enzymes
  2. Inducible ; adaptive and reversible response to the exposure
  3. The substrate specificity is broad and overlapping
42
Q

What is a compound that is a good example of the interspecies differences in detoxification and bioactivation of compounds ?

A

coumarin found in cinnamon

43
Q

What is the reason why coumarin is not toxic to humans while it is for rats

A

Because in humans, coumarin is detoxified by Cyp2A6 enzymes while in rats it is bioactivated into oHPA

44
Q

The biotransformation enzymes will first make the compound ___ in phase I and then in phase II the compound will become more ____

A

phase 1 : more polar
phase 2 : more hydrophilic (for excretion)

45
Q

What is the mode of action of the toxicity of coumarin in rats

A

transformed into toxic metabolite oHPA which induces cell proliferation and induces tumor formation in the liver (without genototoxicity)

46
Q

How can we determine the differences between the species in the metabolism ?

A

with invitro tests for the biotransformation of enzymes by taking rat liver enzymes or human enzymes and then incubating with the compound and then measure then measure the levels of each of the compounds / metabolites formed using HPLC

47
Q

What are the various factors that could explain differences in biotransformation between individuals ?

A
  1. Age
  2. Gender
  3. Genetic variation
  4. Genetic polymorphism
  5. Lifestyle (enzymes are inducable)
48
Q

True of false : the expression CYP enzymes of phase I will change over time

A

true, that also explains why new-borns have different suceptibility to compounds

49
Q

True of False : The levels of phase II enzymes will depend on your age

A

true

50
Q

What is an example of a gender difference in metabolism of compounds

A

Men have more alcohol dehydrogenas (CYP2E1)
Women have more CYP3A4 which is important in the conversion of toxic chemicals

51
Q

The genetic polymorphism can have an important impact on _____ which will impact the ____ of a compound depending on the mode of action of the compound (needs bioactivation or is detoxified by the enzymes)

A

rate of metabolisation
impact on the toxicity of the compound

52
Q

Fast metaboliser will benefit from a lower toxicity of compounds that is ____ by enzymes

A

detoxified

53
Q

Slow metaboliser will benefit from a lower toxicity of compounds that is ____ by enzymes

A

bioactivated

54
Q

Can you give an example of intrspecies differences that lead to more toxicity for slow metabolisers

A
55
Q

What is an example that shows that polymorphism needs to be studied in populations

A

the slow acetylators will have more toxicity from hydralazine which is a drug that lowers blood pressure because the acetylation is the detoxification mechanism.

56
Q

What are the subdivision of the interspecies and intraspecies factors

A
57
Q

Dynamics are more about ____ while kinetics are about ____

A

dynamics : how the chemical infuences the body
Kinetics : how the body influences the chemical (metabolism)

58
Q

CSAF stands for :

A

Compound specific assessment factor

59
Q

Can you give an example of CSAF ?

A

coumarin, the kinetic factor of the interspecies difference could of been reduced from 4 to 0 and so the 100 factor normally attributed could of been reduced by 4 (25%) but some people are difficient in the enzyme (CYP2A6) and can’t detoxify coumarin and so the UF was kept at 100.

60
Q

What does ADME stands for ?

A

Absorption, distribution, metaboism and excretion.

61
Q

What is a way we can study the ADME processes in humans ?

A

using the physiologically based kinetic (PBK) modelling which is a program that can relate the external doses to the internal concentrations

62
Q
A
63
Q
A

Food Toxicology -TOX30306 (9 decks)

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