| Popis: |
The human gastrointestinal (GI) tract is exposed constantly to a variety of xenobiotics, including those derived from the air, diet, and bile, as well as pharmacological agents. The body’s ability to remain healthy despite constant exposure to xenobiotics depends in part on the GI tract’s ability to serve as a protective barrier. The primary component of this barrier is a single layer of cells, which consists predominantly of absorptive columnar epithelial cells, or enterocytes. The enterocytes are replete with biotransformation enzymes and transport proteins that generally act to minimize, or even preclude, the body’s exposure to xenobiotics. Biotransformation enzymes can be categorized as phase I or phase II enzymes. Phase I enzymes consist largely of the cytochromes P450 (CYPs), which either introduce or expose a functional group on the substrate, generally resulting in a small increase in hydrophilicity. Phase II enzymes conjugate organic donor molecules to the substrate, often a CYP-mediated metabolite, and generally result in detoxification and enhanced hydrophilicity of a compound, facilitating excretion from the body. Transport proteins belong to either the ATP-binding cassette or solute carrier superfamilies and are expressed on both the apical (brush border or mucosal) and basolateral (serosal) membrane of enterocytes. As such, these proteins function to facilitate the absorption of xenobiotics from the GI lumen into enterocytes or from enterocytes into the portal circulation, or to facilitate the exsorption of xenobiotics from enterocytes back into the GI lumen. Through the refinement of intestinal cell/tissue models, identification of appropriate animal models, and the increased availability of high-quality human-derived tissue, a comprehensive characterization of GI biotransformation enzymes and transport proteins, as well as their roles in xenobiotic disposition and toxicity, should become feasible. |
