Lecture #4 | Chemical Causes of Cancer: Diet, Chemicals, and Biotransformation

Mechanism #1: Fat may act a a tumor promoter

1. An excess of adipose tissue can cause an increase in FFA (free fatty acids), TNFa (tumor necrosis factor alpha), Resistin, decrease Adiponectin

2. Increases insulin causing insulin resistance, keeping blood glucose high

3. Excessive insulin increasing insulin-like-growth factor 1 causing a decrease in apoptosis and cell proliferation

   

Mechanism #2: Fat enhances free radicals via lipid peroxidation

Lipid peroxidation: poly unsaturated fats are more susceptible to free radicals damage due to double bonds

Chain reactions are created in which 1 free radical can oxidize 20-100 lipid molecules

• free radicals damage DNA and lead to mutations

• lipid radicals can also damage membranes and possibly affect signal transduction → tumor promoter

• produces malondialdehyde which reacts with DNA

Palmitic acid

Lipid that is C16:0 (0 double bonds)

This is a saturated fat

Oleic Acid C18:1

Monounsaturated fatty acid

Linolic Acid C18:2

Polyunsaturated

• essential fatty acids

Makes up cell membranes

• More prone to being

Mechanism of lipid peroxidation

1. If the chain comes in contact with a carbon radical, it becomes rearranged

2. This causes a molecular rearrangement

3. This causes oxygen uptake

The result can degrade

known malondialdehyde

Malondialdehyde (MDA)

Mutagen and carcinogenic compound

• at pH 7.0, reacts with deoxyguanoside to produce M1G-deoxyriobose

• Acts as a DNA adduct causing issues with transcription → mutations

• 5400 adducts per cell → same level of external carcinogen

Fiber correlation to cancer

Americans are consuming too little fiber

• low fiber is associated with a high risk of colon cancer

Cannot be digested by enzymes in our gut

Theories on how fiber decreases colon cancer

1. Insoluable fiber

   1. decreases stool transit time

   2. increases mass of the stool

   3. changes the composition of the bacteria in the gut

   4. changes in gut microbiota are associated with colon cancer

2. Fruits and Vegetables

   1. Americans eating too few fruits and vegetables

   2. low intake are associated wit a risk of colon, breast, prostate, and other cancers

   3. rich in fibers

   4. induce some detoxification enzymes

   5. anti-oxidants

Vitamin A

Retinol, fat soluble, converted from B carotene in orange yellow and dark leafy veggies

• anti-oxidants

• can be stored in body

Vitamin E

Alpha-tocopherol, fat soluble, in olive oil

• protects lipids from peroxidation

• can be stored in body

Vitamin C

l0ascorbic acid, water soluble, in citrus, good at inhibiting formation of nitrosamines

• will be removed

Synthetic anti-oxidants

Preservatives added to meat and other foods to prevent color and flavor change

• thought to protect against chemcially induced cancer in animals

• HOWEVER: at high doses it promotes cancer in animals

BHA: Butylated hydroxyanisole

Synthetic antioxidant

BHT: butylated hydroxytoluene

Synthetic antioxidant

How does nitrosamines increase cancer

Intake of red meat is associated with increased colon cancer

• has high levels of nitrosamines due to preservatives and fertilizers

Very mutagenic

• need to be metabolically activated

Mechanism that converts Nitrates to Nitrosamines

1. Nitrate is converted by micororganisms in the soil and our gut into nitrate

2. Nitrate reacts with secondary amines in acidic environments to produce nitrosamines

Secondary Amines

NDMA

How are nitrosamines activated?

1. Alkylation of the DNA via methyldiazoniom ion

   1. Adds on a -CH3 group

2. Crosslinking via formaldehyde

Metabolism of NDMA

Reagent: NDMA

Product: Hydroxyl ion and methyldiazonium ion

Other than smoking and diet, what is the next most important environmental factor

Chemicals

11% of causes

What is the first recorded link between chemicals and cancer in an occupational setting?

Chimney sweeps in 1775

• recommendation to bathe right after

Occupational exposure

Repeated, high dose exposure that induce significant rates of cancer

• associated with specific occupations

• lower doses may also affect certain susceptible members of the general population, but it is more difficult to see the correlations with lower doses

How many chemical compounds are human carcinogens

256 (2021 data) chemical compounds are known or anticipated to be human carcinogens

• 63 known human carcinogens

• 193 reasonably anticipated human carcinogen

New:

• Helicobacter: bacterium known for stomach cancer

• Antimony trioxide: synergist for flame retardants

• 6 halo acetic acids: byproduct of disinfectants

Xenobiotics

Foreign (xeno) compounds that affect organisms

• synthetic or natural (plants)

• things that u eat or are otherwise exposed to

• can be both water soluble or lipophilic

  • Nonpolar lipophilic are of greatest concern because they can easily get passed cell membrane

Major routes of absorption for xenobiotics

Skin, lung, and gut

What happens when a xenobiotic enters the body

Depends on the chemical structure and its initial site of absorption

• Liver is the major detoxification organ

• all ingested compounds go from the intestines to the liver via total vein

Metabolism of xenobiotics

Carried out primarily in the liver

• also in kidney, lungs, and intestines

• somewhat in skin, testes, placenta, and adrenals

How does xenobiotic detoxification vary based on chemical structure?

• Polar/volatile compounds: Not changes → directly excreted

• Nonpolar compounds → metabolized → makes them more water soluble

Goal is to detoxify and excrete compounds BUT sometimes intermediates are formed to make carcinogens

Primary types of biotransformation

1. Phase 1 reactions

2. Phase 2 reactions

Phase 1

• Expose a reactive polar functional group in lipophilic compounds

• add a chemical handle to make it more portal

  • hydroxylation

  • epoxidation

  • reduction

  • addition of a sulhydridyl

  • addition of hydroxyl amines

    

Cytochrome p450 enzymes (mixed functional oxidases)

Enzymes that primarily carry out phase 1 reactions

• superfamily of enzymes

• all contain a cytochrome that absorbs light

• present in all organisms from bacteria to man

  • ex: CYP3A metabolizes most dugs but grapefruit inhibits activity

• Act on endogenous and exogenous substates

  • Regulates endogenous compound like steroids

  • removes exogenous compounds derived from other species

• Constitutive and inducible

  • constitutively expressed in the liver

  • some are induced by the compound they act on or foods or antibiotics

• Acts on many different substrates

  • Activity can’t be eliminated

Polycyclic aromatic hydrocarbons

Classical example of compounds that require metabolic activation by P450 enzymes

• highly mutagenic compounds

• must be metabolically activated

  • found in:

    • Coal tar

    • grilled and charcoal broiled meats

Benzo[a]pyrene

Best studied PAH

• cigarette smoke, exhaust, charbroiled meat

• HAS to be metabolized first by p450

  • Aromatic amino acids are converted to PAHs at high heat

  • Idole ring (Trp, Pro) inhibits the formation of PAH

• Grains soy protein and pectin decrease the mutagen formation in hamburgers

Metabolism of BAP

1. BaP is acted on by the P450 family members

2. Adds an oxygen and converts BaP-7,8-epoxide

3. Breaks up to a diol

4. Forms a BPDE (mutagenic)

5. Creates an adduct which interacts with DNA, allowing for more mutations