Human exposure to pollutants. Pollutants in the air, water, and soil are absorbed through the lungs, gastrointestinal tract, and skin. In the body they may act at the site of absorption but are generally transported through the bloodstream to various organs where they may be stored or metabolized. Xenobiotics may be metabolized to water-soluble compounds that are excreted, or to toxic metabolites, a process referred to as activation.
A, Xenobiotics can be metabolized to nontoxic metabolites and eliminated from the body (detoxification).
B, Xenobiotic metabolism may also result in the formation of a reactive metabolite that is toxic to cellular components. If repair is not effective, short- and long-term effects develop.
What is the most important catalyst of Phase I reactions?
The Cytochrome P-450 enzyme system (CYP)
The P-450 system catalyzes reactions that either detoxify xenobiotics or, less commonly, convert xenobiotics into active compounds that cause cellular injury.
These types of reactions produce ROS.
Inducers of CYP bind nuclear receptors which heterodimerize with retinoic X receptor (RXR) to form a transcriptional activation complex that associates with promoters.
CYP inductor responses:
- aryl hydrocarbon receptor
- peroxisome proliferator-activated receptors (PPAR)
- Two orphan nuclear receptors: constitutive androstane receptor (CAR), and pregnane X receptor (PXR)