Week 1 - Biotransformation + carcinogens

Question 1

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

Answer 1

3

Question 2

why does mutagenicity doesn’t equal carcinogenicity ?

Answer 2

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)

Question 3

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

Answer 3

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

Question 4

_____ is a non-genotoxic carcinogen in cinnamon

Answer 4

coumarin

Question 5

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

Answer 5

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

Question 6

carcinogenicity of estragole and methyleugenol is related to____

Answer 6

DNA adduct formation

Question 7

Can you explain the mechanism by which methyleugenol becomes genotoxic ?

Answer 7

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

Question 8

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

The MOE is nota quantitative risk assessment

Answer 8

true

Question 9

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

Answer 9

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

Question 10

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

Answer 10

alkenylbenzene
genotoxic because of DNA adduct formation

Question 11

What are the three categories of unavoidable carcinogens seen in class

Answer 11

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

Question 12

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

Answer 12

pyrrolizidine alkaloids

Question 13

pyrrolizidine alkaloids carcinogenicity mode of action is throught

Answer 13

formation of DNA adducts

Question 14

____ is a mycotoxin produced by _____ (mold)

Answer 14

aflatoxin B1 produced by the aspergillus flavus mold

Question 15

What is the mode of action of aflatoxin B1 ?

Answer 15

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

Question 16

t or f : Aflatoxin B1 needs biotransformation to be genotoxic

Answer 16

true, it is the epoxide of aflatoxin that is genotoxic

Question 17

T or F : the MOE of Aflatoxin B1 raises concern

Answer 17

true since it is at 88-483

Question 18

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

Answer 18

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

Question 19

T or F : nitroamines is a problem for young children

Answer 19

true, their MOE is under 10 000

Question 20

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

Answer 20

PAH : pyrolysis
Acrylamide and heterocyclic amines : Maillard reactions

Question 21

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

Answer 21

Phip, also known as the hamburger carcinogen

Question 22

the lowest BMDL10 for PhIP can give ____ tumors

Answer 22

prostate tumors

Question 23

T or F : heterocyclic amines are high priority

Answer 23

false, they have a MOE of 15 000

Question 24

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

Answer 24

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

Question 25

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

Answer 25

false, it is the other way around

Question 26

\_\_\_\_\_ are found in coffee, canned and jarred foods

Answer 26

furans

Question 27

How are furans formed

Answer 27

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

Question 28

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

Answer 28

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

Question 29

Are furans a concern ?

Answer 29

yes because the MOE is at 36-582

Question 30

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

Answer 30

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

Question 31

How does brocoli reduces the aflatoxin toxicity ?

Answer 31

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

Question 32

How does isothocyanates reduces the oxidative stress ?

Answer 32

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

Question 33

What is the step in ADME that explains the interindividual differences

Answer 33

The biotransformation

Question 34

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

Answer 34

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

Question 35

What are the two phases of biotransformation ?

Answer 35

* *Phase 1** : modification to make the compound polar * *Phase 2** : conjugation to make the compound hydrophilic

Question 36

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

Answer 36

1. Oxidation 2. Reduction 3. Hydrolysis

Question 37

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

Answer 37

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

Question 38

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

Answer 38

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

Question 39

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

Answer 39

1

Question 40

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

Answer 40

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

Question 41

Why are three reasons explaining the broad substrate specificity ?

Answer 41

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

Question 42

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

Answer 42

coumarin found in cinnamon

Question 43

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

Answer 43

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

Question 44

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

Answer 44

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

Question 45

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

Answer 45

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

Question 46

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

Answer 46

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

Question 47

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

Answer 47

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

Question 48

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

Answer 48

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

Question 49

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

Answer 49

true

Question 50

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

Answer 50

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

Question 51

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)

Answer 51

rate of metabolisation impact on the toxicity of the compound

Question 52

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

Answer 52

detoxified

Question 53

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

Answer 53

bioactivated

Question 54

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

Answer 54

Question 55

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

Answer 55

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

Question 56

What are the subdivision of the interspecies and intraspecies factors

Answer 56

Question 57

Dynamics are more about ____ while kinetics are about \_\_\_\_

Answer 57

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

Question 58

CSAF stands for :

Answer 58

Compound specific assessment factor

Question 59

Can you give an example of CSAF ?

Answer 59

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.

Question 60

What does ADME stands for ?

Answer 60

Absorption, distribution, metaboism and excretion.

Question 61

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

Answer 61

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