Chapter 11: Nutrients, hormones, and gene interactions (Lecture, main)

Question 1

What is a dangerous risk for cancer?

Answer 1

Being overweight or obese.

Question 2

Several mechanisms that occur when obese are mentioned in the book that contribute to cancer. Name four of these mechanisms.

Answer 2

1. Sex hormone metabolism
2. Increased adipocyte hormone (adipokines)
3. Increased insulin signaling pathways.
4. Dietary alterations in the gut microbiota.

Question 3

How does the metabolism of sex hormones (estrogen) when obese contribute to cancer?

Answer 3

The amount of fat cells are (of course) higher in people who are overweight/obese. These fat cells contain the enzym aromatase, an important enzyme in the production of estrogen. So there’s increased aromatase and therefore increased estrogen production, which has carcinogenic properties.

Question 4

How does an increase in adipocyte hormones (adipokines) when obese contribute to cancer?

Answer 4

Obesity and overweight correlate with a chronic inflammatory response which produce tumor promoting cytokines (adipokines).

Question 5

How does an increase in the insulin signaling pathways when obese contribute to cancer?

Answer 5

The large amounts of adipose tissue releases large amounts of free fatty acids (FFA). FFA stimulates insulin release ((by stimulating insulin secretion or by decreasing insulin clearance)) where the high insulin levels have tumorigenic effects.

Question 6

How do dietary alterations in the gut microbiota when obese contribute to cancer?

Answer 6

Since the gut microbiota change (more gram+ bacteria), more bile acids will be metabolized to deoxycholic acid. This results in liver DNA damage.

Question 7

The professor discusses the current human development in regard to obesity. I think these powerpoint slides are either ‘common knowledge’ or easy to answer. So therefore, go to the deck with secondary details, for some questions regarding this subject.

Answer 7

Ok

Question 8

Fill in: An unhealthy diet can cause … (1). And … (1) can cause cancer, but also … (2) and … (3). This also works the other way around where a healthy diet can reduce the risk of these disorders/diseases.

Answer 8

An unhealthy diet can cause obesity (1). And obesity (1) can cause cancer, but also cardiovascular disease (2) and Diabetes Mellitus type 2 (3). This also works the other way around where a healthy diet can reduce the risk of these disorders/diseases.

1. Obesity 2. Cardiovascular disease 3. Diabetes mellitus type 2

Question 9

For what is food used in our body?

Answer 9

For energy, as precursors for biosynthetic reactions, for enzyme function and for protection from free radicals.

Question 10

What do epidemiological and animal studies show in regard to the bioactive substance beta-carotene (pro-vitamin A)?

Answer 10

These studies suggest that beta-carotene in certain fruits and vegetables have a protective effect against cancer.

Question 11

The Alfa-Tocopherol Beta-Carotene cancer prevention study (ATBC) is a RCT to examine the effects of vitamin E and beta-carotene supplementation on reducing the incidence of lung cancers in male smokers, ages 50-69 years. What what the conclusion in this study?

Answer 11

That vitamin E and beta-carotene supplementation resulted in increased lung cancer in smokers.

Question 12

Name three other causative factors (other than obesity) of cancer.

Answer 12

1. Carcinogenic contaminants 2. Dietary deficiencies 3. Alcohol consumption

Question 13

What carcinogenic contaminant is produced during fire, in industry, in cigarette smoke, car exhaust and in burnt foods?

Answer 13

Polycyclic aromatic hydrocarbons e.g. benzo(a)pyrene

Question 14

Why can nitrate rich vegetables (spinach, lettuce, beetroot, endive) be dangerous/cancer causing?

Answer 14

Because bacteria produce nitrite from nitrate, nitrite is a “risk factor” for cancer development. Therefore storing and reheating of these vegetables seem to be a problem. (This doesn’t nessecarily mean that you cannot eat these vegetables. Study shows when these vegetables are cooled down quickly and stored less than 2 days at 4°C, they are safe to be eaten/reheated).

Question 15

How can red/processed meat cause intestinal or lung cancer?

Answer 15

Due to the high levels of heam iron in red/processed meats. These high levels contribute to the production of nitrosamines and its’ carcinogenic effects.

Question 16

What happens when you cook meat at a high temperature?

Answer 16

Heterocyclic amines and DNA adducts will form which will cause base substitutions and mutations.

Question 17

Aflatoxin B is a fungal product in peanuts. What specific cancer can result from exposure to aflatoxin B and through what kind of mutation will this usually occur?

Answer 17

It causes GC to TA transversions which can cause liver carcinomas.

Question 18

Food preservatives can also be carcinogenic contaminants. Name a preservatif that is a carcinogenic contaminant and explain what it does in the body.

Answer 18

Sodium nitrite, it may produce carcinogenic N-nitroso compounds.

Question 19

How can salmon become a carcinogenic contaminant?

Answer 19

Because salmon is a fatty fish where pollutants can accumulate. These genotoxic pollutants can be passed down to humans who consume salmon.

Question 20

Folate is a co-enzyme that first needs to be activated by another enzyme called MTHFR. What is the normal function of folate?

Answer 20

Folate (vitamin B) is a co-enzyme that is needed for nucleotide synthesis and DNA methylation.

Question 21

How can a folate deficiency result in an increased risk for colorectal cancer (give two reasons)?

Answer 21

Low folate means low DNA methylation, which is already the first reason why a folate deficiency can cause cancer. The other reason why this is has to do with the fact that with the help of the enzyme MTHFR, dUMP is converted to dTMP. Since folate is important for nucleotide synthesis, MTHFR needs folate to convert dUMP to dTMP. With a folate deficiency, there’s not enough folate for dTMP synthesis. dUMP accumulates, causing DNA damage and an increase in the risk for cancer.

Question 22

How can chronic alcohol consumption lead (for example) an increased risk for mouth cancer?

Answer 22

The enzyme alcohol dehydrogenase converts alcohol to acetaldehyde. Acetaldehyde can bind to DNA to form DNA adducts, which cause mutations. Bacteria in saliva can be very active in this process which causes an increased risk for mouth cancer.

Question 23

A certain single nucleotide polymorphism (SNP) in the acetaldehyde dehydrogenase is common in Asians. What does this SNP result in?

Answer 23

A low enzymatic activity of acetaldehyde dehydrogenase, which causes an alcohol intolerance which causes an increased risk for esophageal cancer.

Question 24

What is an example of a preventative factor for cancer?

Answer 24

Constituents of fruits and vegetables.

Question 25

Preventative factors like fruits and vegetables prevent cancer by blocking DNA damage caused by ROS and/or carcinogens. They do this by three mechanisms, what three mechanisms (these mechanisms will be discussed shortly)?

Answer 25

1. Directly by free radical scavengers
2. Indirectly by regulating gene expression of phase I & II metabolizing enzymes.
3. Apoptosis and cell proliferation modulation

Question 26

How is DNA damage prevented through the use of free radical scavengers?

Answer 26

ROS scavengers are antioxidants (like vitamin C and E) that donate electrons to free radicals, inhibiting reactivity and chain reactions of those free radicals.

Question 27

Vitamin C and E are both antioxidants that work as ROS scavengers. But they do have different properties and therefore different functions. Describe these.

Answer 27

Vitamin C is a water soluble vitamin (and can also be regerated by vitamin C reductase) while vitamin E is a fat soluble vitamin. Therefore vitamin E can help in e.g. membranes, where vitamin C can not.

Question 28

Now moving onto preventing DNA damage caused by toxins by regulating gene expression of phase I & II metabolizing enzymes. Our metabolism is divided into three phases (oxidation, conjugation and elimination). Can you explain these three phases (and what enzymes are needed for these phases)?

Answer 28

• Phase I is where (fat-soluble) toxins are oxidated, this is typically done by Cytochrome P450.
• Phase I toxins enter phase II and will be conjugated to hydrophillic products by glutathione S-transferases.
• The toxins can now enter Phase III where they will be eliminated from the body via bile or urine.

Question 29

So please look at this figure and try to understand what’s going on. In this picture is depicted how gene expression of metabolizing enzymes is regulated in a non-stressed cell and stressed cell.

Answer 29

Okay

Question 30

Briefly explain the function of the following components in regard to the regulation the gene expression of metabolizing enzymes:

1. Antioxidants
2. Carcinogens (H2O2 and reactive elecrophilic intermediates)
3. Antioxidant Response Element (ARE)
4. Nrf2
5. KEAP1
6. Maf

Answer 30

1. Antioxidants can regulate the gene expression of metabolizing enzymes (by inhibiting Nrf2 degradation).
2. Carcinogens can do the same as the antioxidants.
3. ARE is a response element in the promotor region of genes for metabolizing enzymes.
4. Nrf2 is a transcription factor that can bind to ARE to induce gene expression
5. KEAP1 contains cysteines that can sense the redox state of the cell. It can then steal Nrf2 from DNA, causing degradation of Nrf2.
6. Maf is a cofactor and when Nrf2 and Maf are bound, gene expression is induced.

Question 31

In a normal non-stressed cell KEAP1 pulls Nrf2 from the ARE in the genes of the metabolic enzymes and tags it for degradation, so that transcription cannot be induced. How can carcinogens or antioxidants activate this Nrf2-Are signaling pathway and with this the metabolic enzymes?

Answer 31

Carcinogens or antioxidants can bind to the cysteine residues in KEAP1. This inhibits the function of KEAP1 so that Nrf2 stays on the ARE of the metabolic enzyme genes. Nrf2 then binds to cofactor Maf which causes induction of gene expression.

Question 32

Garlic contains several substances that have a preventative function (scavenging, enzymes or apoptosis/proliferation). Examples of these substances are organosulfur (1), ajoene (2) and allicin (3). Describe if these substances have a function in scavenging, enzymes or apoptosis or proliferation.

Answer 32

1. Organosulfur is important in scavenging and phase II enzymes
2. Ajoene is important in apoptosis (it activates caspases and stimulates production of peroxide)
3. Allicin inhibits proliferation of human cells.

Question 33

EGCG is a component in green tea. What role does EGCG have in one of the three preventative mechanisms?

Answer 33

EGCG is involved in apoptosis/cell proliferation (but also metabolic enzymes). It can bind to DNA methyltransferase, then blocks cytosine entry, prevents methylation, blocks telomerase activity and limits replicative capacity of cells.

Question 34

There seem to be inconsistent results regarding dietary fibers and its (possible) protective features. Name 4 ways dietary fibers can inhibit carcinogenesis.

Answer 34

1. They induce dilution and adsorption of carcinogens in intestinal lumen.
2. They induce modulation of colonic microbial metabolic activity.
3. They induce modification of intestinal epithelial cells.
4. They bind minerals, which may inhibit carcinogenesis.

Question 35

There seem to be inconsistent results regarding dietary fibers and its (possible) protective features. What is an inconsistent result that shows that it may act carcinogenic?

Answer 35

That fibers fermentate in the large bowel, which produces SCFA. This substances stimulates cell proliferation in vivo.

Question 36

Like all cells, cancer cells need glucose to function. Normal cells break down glucose in the presence of oxygen (aerobic) without producing lactate. Glucose in cancer cells is broken down in aerobic conditions, but with the production of lactate. How is his called?

Answer 36

The Warburg effect.

Question 37

How do tumor cells affect the micro environment in order to affect the immune response to the tumor cells?

Answer 37

They use glycolysis in order to lower the extracellular glucose. This reduces glycolysis and the function of tumor-infiltrating T cells.

Question 38

Resveratrol (a polyphenol in grapes and wine) can act as a tumor suppressor. How?

Answer 38

Resveratrol inhibits the Warburg effect (so a tumor can no longer affect the micro environment and the immune respons).

Question 39

How does hypoxia contribute to cancer cell function?

Answer 39

Hypoxia (or oncogenic mutations) activates HIF-1a. HIF-1a inhibits Krebs cycle and oxidative phosphorylation and stimulates glycolytic enzymes (glycolysis).

Question 40

How does hypoxia prevent cancer cell function?

Answer 40

Through exercise or starvation hypoxia increases. This causes a decrease in energy (ATP), but an increase in AMP. AMP (but also LKB1) activates AMPK. AMPK activates p53 and can inhibit mTOR (which stops cell growth and cell survival).

Question 41

What is nutrigenics?

Answer 41

The study of genetic polymorphisms that alter the response to a particular dietary constituent.

Question 42

N-Acetyltransferases catalyze the acetylation of aromatic amines and hydrazines. How can the rapid type of N-acetyltransferase in combination with lots of red meat cause a high risk for colon cancer?

Answer 42

Because cooking red meat at high temperatures produces heterocyclic amines. A rapid type of N-acetyltransferase that can rapidly catelyze acetylation of amines can thus create a high risk for colon cancer.

Question 43

How will a tyrosine deficiency result in an increased risk for skin carcinoma?

Answer 43

With a tyrosine deficiency there’s no melanin production (albino). This causes the increase in cancer risk.

Question 44

What is fumarylacetoacetate hydrolase deficiency (tyrosinemiatype 1)?

Answer 44

A deficiency that causes carcinogen production and accumulation.

Question 45

Vitamin D3 is the precursor of vitamin D and can be found in sunlight (as 7-dehydrocholesterol) and dietary products (fish, meat and supplements) (as Vitamin D3 or D2). 1,25-dihydroxyvitamin D3 is the active form of vitamin D. What needs to happen in order for precursors in sunlight or in dietary products to be converted into the active form of vitamin D?

Answer 45

During sunlight exposure, 7-dehydrocholesterol is converted into vitamin D3 (cholecalciferol). Vitamin D3 (or D2) from dietary products or sun are then converted by the liver into 25-hydroxyvitamin D3. 25-hydroxyvitamin D3 is then converted by the kidneys to the active form of vitamin D (1,25-dihydroxyvitamin D3).

Question 46

Activated vitamin D (1,25 dihydrovitamin D) is a steroid hormone and can acts as a chemopreventative agent. How is it chemopreventative?

Answer 46

Because it inhibits growth and induces differentation and apoptosis.

Question 47

Why is it that vitamin D & A are easily toxic by overdosing?

Answer 47

Because these vitamins directly affect gene expression (see picture).