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.
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.
To see again the animation of transcriptional activation mechanism of nuclear receptors shown in the previous e-lecture on Vitamin A, click here:
Although the function of the phase I enzymes is protective, as a side effect they may convert some pro-carcinogens (e.g. benzo