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6. MODULATION OF DNA DAMAGE (I) Xenobiotic metabolising systems

Xenobiotic metabolism - deals with toxic chemicals

Metabolism = biotransformation (The conversion of a chemical from one form to another)

Xenobiotic metabolism occurs in liver, and to some extent in the GI tract, kidneys, lungs and skin.

  • Phase I reactions

Cytochrome P450 (CYP) oxidase enzymes - many types of enzymes acting on different classes of chemicals.
CYP450 enzymes are also known as mixed-function oxidases.
They oxidise organic compounds that are potentially toxic to more reactive (more water-soluble) forms as the first step in their disposal.

http://meddev.uio.no/elaring/lcms13/ernaeringslaere/nutr-cancer-biology/illustrations/CYP3A4.jpg

The level of CYP enzymes is tightly regulated at the DNA level.
The production of many CYP enzymes is induced by the chemicals that they oxidise - they are inducible by their substrates.
In this way, the presence of a toxin leads to its own degradation.

Gene expression is regulated by e.g. specific nuclear receptors such as SXR - Steroid and Xenobiotic Receptor

As explained in previous e-lectures, nuclear receptors (NRs) constitute a large group of transcription factors that regulate the expression of a large array of genes.
The nuclear receptors are activated by specific ligands before they regulate the expression of their target gene.
Some nuclear receptors have a variety of drugs and toxins as ligands, and therefore serve as sensors for xenobiotics.

http://meddev.uio.no/elaring/lcms13/ernaeringslaere/nutr-cancer-biology/illustrations/SXR_act.jpg

ANIMATION

To see again the animation of transcriptional activation mechanism of nuclear receptors shown in the previous e-lecture on Vitamin A, click here:
START ANIMATION

Although the function of the phase I enzymes is protective, as a side effect they may convert some pro-carcinogens (e.g. benzoapyrene, aflatoxin) to a reactive form that is carcinogenic.