Lecture #5 | Chemical Causes of Cancer III Phase II, Phytochemicals, Aflatoxin B1, Dioxin and AhR Receptor-mediated toxicity

Phase II reactions

Conjugated reactions (chemically linked) to create a conjugate

Conjugates are:

1. Glucuronides: most common, sugar + nucleotide

   

2. Glutathione: peptide (Glu-Cys-Gly)

3. Sulfhydryl-SH

Conjugation with glucuronide

Sugar + Nucleotide interacts with a xenobiotic that has already went through Phase 1 (has a polar group)

1. A transferase will mediate the xenobiotic with the glucuronide

2. Molecule is too big and will be targeted for removal

Conjugate with gluthathione

Binds to electrophiles due to SH group in system to help remove radicals

Beneficials

1. Detox

2. Antioxidant

3. Protects against environmental toxin

Harm

1. Cancer Risk due to stoppage of apoptosis

2. May block chemotherapy drugs

Compounds that induce Phase 1 and Phase 11

Constitutive and inducible forms of both Phase 1 an phase 2 enzymes

• example of both is phytochemiclas

Monofunctional: induce just phase 2

Bifunctional: induces Phase 1 and 2

Phytochemicals

Chemicals in plants

• help prevent cancer

• impact has 1/11

  • Flavonoids: major class

    • Water soluble pigments

    • Can decrease risk of variety of cancers

Curcurmin

Phyochemical from turmeric

Capsaicin

Phyochemical from chili peppers

Epigallocatechin-3-gallate

phytochemical from green tea

• flavonoids

Genistein

Phytochemical from soybeans

• flavoidoids

Lycopene

Phytochemical found in tomatoes

Resveratrol

Phytochemical found in grapes

• inhibits all 3 stages of cancer

Indole-3-carbinol

phytochemical found in cabbage

Sulphoraphane

Phytochemical found in broccoli

Flavones

mechanisms for chemopreventative properties of phytochemicals

1. induced detoxification enzymes (both phase 1 and 2)

2. blocks the formation of carcinogens by acting as anti-oxidants

3. act as a tumor suppressing agents

4. antagonize the effects of estrogens → growth

5. stimulate DNA repair

How do phytochemicals act as anti-carcinogens

1. Increasing carcinogens detoxification

2. Suppressing the chemical activation of procarcinogen to ultimate carcinogen

3. Suppressing the promotion and progression of carcinogen

Alfatoxin B1

Produces by a mold that lives on peanuts and corn

• mainly found in Africa and Asia

• Originally identifies in England

• Metabolically activated to a carcinogen by P450 enzyme

• 100x more mutagenic and carcinogenic than B[a]P

Metabolic activation of aflatoxin B1

1. Alfatoxin is ingested and converted into aflatoxin B1-8,9 oxide by P450 through a phase 1 reaction

2. If it is acted upon by epoxide hydrase (water added), it is detoxified

3. If it comes into contact with glutathione S-transferase it can undergo a phase 2 via GST (also not harmful)

However, aflatoxin B1-8,9 oxide by itself is very unstable and has a tendency to form a DNA adduct

• once adduct forms, it can lead to p53 which is a tumor suppressor

HBV (hepatitis b virus) infection

Acts as a tumor promoter, inducing a cell proliferation in the liver

• increased proliferation of cells containing AFB1 adducts in DNA means less time for repair

  • More mutations

Dioxin

• complete carcinogen

• linear dose response

  • Low doses do matter, do accumulate

Environmental exposure of Dioxins

Never made commercially but byproducts of

• Plastics, bleach, antiseptics

• Incomplete combustion

  • chlorinated wastes

  • wood burning

• Major increase after 1940s

Bioaccumulation of dioxins

Concentrate in the food chains and make its way to humans

• from meat and dairy products

Some dioxins are present in every person on the planet

• average body burn is 5-50pg/gr of body fat

Good news about dioxins

Annual emission of dioxins decreased 90% from 1987 to 2000 due to EPA regulations

• decrease in intake of dioxins

Epidemiology of dioxins

Classified as a known human carcinogen in 1997

• 1976 explosion at chemical plats in Italy

• released 3 kg of TCDD (2x annual emissions in the US in 2000)

• increase in liver cancer and myelomas but decrease in breast and endometrial cancer

Fate of xenobiotics in the body