Humans are constantly in contact with a variety of xenobiotics. The gastrointestinal (GI) tract forms an important initial functional barrier, in addition to its critical role in absorbing nutrients. An understanding of the structure, physiology, and enteric autonomic system is critical to toxicologic concepts of absorption, gastric motility and appreciating the unique vulnerabilities of the GI tract to xenobiotics. This chapter discusses the role of the GI tract and its relation to toxicology. Anatomic, pathologic, and microbiologic principles are discussed, including the role of the GI tract in the metabolism of xenobiotics. Examples of GI pathologies and their clinical manifestations are discussed.
The luminal gastrointestinal tract can be divided into five distinct structures: oral cavity and hypopharynx, esophagus, stomach, small intestine, and colon. These environments differ in luminal pH, specific epithelial cell receptors, and endogenous flora. The transitional areas between these distinct organs have specialized epithelia and muscular sphincters with specific functions and vulnerabilities. Knowledge of the anatomy of these transition zones is particularly important to the localization and management of foreign bodies. The functions of the pancreas and liver are closely integrated with those of the luminal organs, although they are not within the nutrient stream. The pancreas is discussed here; the liver and its metabolic functions are discussed in Chapters 12 and 26.
The visceral structures of the GI tract are composed of several layers, including the epithelium, lamina propria, submucosa, muscle layers and serosa (the last only in intraperitoneal organs). As the transition is made throughout the GI tract differences in luminal pH, epithelial cell receptors, muscularity and endogenous flora are encountered, affecting absorption and metabolism of individual xenobiotics.
The epithelium, the innermost layer of the GI tract, is the most specialized cell type in the intestine and is composed of epithelial, endocrine and receptor cells. Epithelial cells have polarity, with the basal surface facing the lamina propria and the apical surface facing the lumen. They are further specialized for specific functions of secretion or absorption. Additionally, the epithelial cell forms part of the mucosal immune defense, to detect the presence of microbial pathogens and down-regulate the immune system in the presence of nonpathogenic or probiotic microbes. The major barrier to penetration of xenobiotics and microbes is the GI epithelium, a single cell thick membrane.13 The cell membrane is a lipid bilayer that contains proteins, which act as aqueous pores through which certain materials can pass, dependent on size or molecular structure, providing the basis for semi-permeability. The membrane is not continuous as it consists of individual epithelial cells; however, these cells are joined to each other by structures known as tight junctions, which are located on the lateral surfaces of the cells, near the apical membranes. The tight junctions have a gap of about 8 angstroms, which allows passage only of water, ions, and low-molecular weight substances.
The muscle layer found beneath the lamina propria is made up of ...