Xenobiotics are compounds that are foreign to a living system. Toxic xenobiotics interfere with critical metabolic processes, cause structural damage to cells, or alter cellular genetic material. The specific biochemical sites of actions that disrupt metabolic processes are well characterized for many xenobiotics although mechanisms of cellular injury are not. This chapter reviews the biochemical principles that are relevant to an understanding of the biotransformation enzymes and their clinical implications and the damaging effects of toxic xenobiotics.
XENOBIOTIC CHARACTERISTICS AND TOXICITY
The capacity of a xenobiotic to produce injury is affected by many factors, including its absorption, distribution, elimination, genotypic/phenotypic states, synergistic/antagonistic coingestants, site of activation or detoxification, and site of action. This section focuses on how the route of exposure (absorption) and the ability to cross membranes in order to access particular organs (distribution) affect toxicity.
The route of exposure to a xenobiotic often confines damage primarily to one organ, for example, pulmonary injury that follows inhalation of an irritant gas or gastrointestinal (GI) injury that follows ingestion of a caustic. However, most xenobiotics have lipophilic properties that facilitate absorption across cell membranes of organs that are portals of entry into the body: the skin, GI tract, and lungs. Systemically circulating xenobiotics, such as cyanide or carbon monoxide, affect toxicity in multiple organs. The liver is particularly susceptible to xenobiotic-induced injury as it receives blood supply from both the portal venous system and from the hepatic artery containing xenobiotics absorbed from multiple sites of exposure.
Once systemically absorbed, various factors affect the distribution of a xenobiotic to a particular organ, including its molecular weight, protein binding, plasma pH/drug pKa, lipophilicity, in addition to the presence of membrane transporters, and physiologic barriers (Chap. 9). Restriction of distribution or preferential distribution into a target organ determines the ability of a xenobiotic to mediate tissue injury. For example, many potentially toxic xenobiotics fail to produce central nervous system (CNS) injury because they cannot cross the blood–brain barrier. The negligible CNS effects of the mercuric salts when compared with organic mercury compounds are related to their relative inability to penetrate the CNS. With respect to target organs, 2 potent biologic xenobiotics—ricin (from Ricinus communis) and α-amanitin (from Amanita phalloides)—block protein synthesis through the inhibition of RNA polymerase. However, they result in different clinical effects because they access different tissues. Ricin has a special binding protein that enables it to gain access to the endoplasmic reticulum in GI mucosal cells, where it inhibits cellular protein synthesis and causes severe diarrhea. α-Amanitin is transported into hepatocytes by bile salt transport systems, where inhibition of protein synthesis results in cell death. Finally, the electrical charge of a xenobiotic at tissue pH affects its ability to enter a cell. Unlike the ionized (charged) form of a xenobiotic, the un-ionized (uncharged) form is often lipophilic and passes through lipid cell membranes ...