Lecture 6 | Chemical Causes of Cancer IV Aryl Hydrocarbon Receptor (cont) Pesticides

Mechanism of action of Dioxin

Not genotoxic: does not interact directly with DNA, does not cause mutations (directly)

• acts epigenetically via a protein receptor

• Aryl hydrocarbon receptor (AhR)

  • can bind dioxin and other aromatic hydrocarbons

  • Once bound to a ART, it dimerizes into AhR:ARNT heterodimer

    • This dimer binds DNA at xenobiotic response elements (XRE)

  • Regulates transcription of genes involved in xenobiotic metabolism cell proliferation and differentiation

  • Highly expressed in the liver

Transcriptional activators and repressors

ex: Ah receptor

Binds specific DNA elements upstream of the start site of transcription nd regulate transcription

Dioxin mechanism

Regulates expression of drug/xenobiotic metabolism genes by binding ti AhR

• cannot go into cell by itself

• so it binds to AhR

• comes into contact with nucleus transporter and is directed to Arnt

  • Found upstream of transcription start site

  • Bind to the XRE of the Cyp1a1 gene

  • This will increase transcription of Cyp1a1 → allows more phase 1

  • Bad outcome

Transcriptional targets of Ah Receptor

Activated genes involved in both phase 1 and phase ii

phase 1:

• dioxin acts indirectly as an initiation

phase 2:

cell proliferation and differentiation:

• dioxin acts as a tumor promoter

Therefore Dioxin is a complete carcinogen

Exogenous ligands for AhR

Flavonoids, carotenoids, indole-3-carbinol, resveratrol

• all AhR agonists/antagonists

Impact of AhR depends on what binds to it

Endogenous AhR ligands

AhR is best known for binding exogenous, carcinogenic compounds like BaP and dioxin but:

• Products derived from Trp

• Virulence factors

• Possible part of a defense system to bacterial infections

Receptor-mediated effects of dioxin are pleiotropic and synergistic with other carcinogens

If dioxin exposure occurs at the same time as Aflatoxin B1 then:

1. dioxin activates AhR which increases Cyp1A2

2. In combo with aflatoxin B1 they produce harmful AFB1-8,9oxide which is a DNA adduct which causes cell proliferation genes

So impacting phase 1 enzymes and cell proliferation genes

• causes increased mutagenic carcinogenic

what is u are also eating phytochemicals

• can also activate AhR which will decrease impact of AFB1-8,9

B[a]P interactions with dioxin

Ligand for AhR

• exhibits both genotoxic and non genotoxic effects

• Stimulates its own metabolism

Genetic variation in Phase 1 and 2

Pesticides

Non genotoxic carcinogens and are classified as tumor promoters

• Usage: insecticides, fungicides, herbicides, rodenticides

Bad: increasing worldwide

• due to increased demand for food

Good news: decreasing US

• Usage in the US

  • Peaked 1981

Pesticides adverse health effects

1. General population: exposure in food

2. Bystander exposure: home, serial drift

3. Occupational

4. Poisionings

3 milllion agricultural workers left with health effects

Problem with testing

1. Inadequate testing: most testing done by the companies that produce the pesticides

2. long term effects on general population are not known

3. tolerance levels are often set too high

4. raw and processes food are not treated the same

5. not having an accurate measurement of total human exposure