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The liver performs many functions that are critical to life. Among these are the processing of foods and other substances absorbed from the intestinal tract and the subsequent delivery of processed nutrients to other organs in the body. The liver is also an integral contributor of immunity that protects mammals from harmful pathogens. In addition to its immunological roles, it is the main organ where exogenous chemicals are metabolized, a process that hastens their excretion into bile and urine. As a consequence, liver cells are exposed to significant concentrations of these chemicals and their metabolites, some of which can cause liver dysfunction. Many industrial chemicals, plant toxins, environmental pollutants, food-borne agents, herbal remedies, and drugs (both pharmaceutical and recreational) are known to be hepatotoxic. In the pharmaceutical industry, adverse effects on the liver are one of the most frequent reasons for discontinuing the development of drug candidates and withdrawal of drugs from the market (Temple and Himmel, 2002; Stickel et al., 2011).
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Although many hepatotoxic chemicals have been identified in the last several decades and much has been learned about mechanisms by which liver toxicity occurs, liver injury from various chemicals continues to present major health concerns. The liver comprises several cell types, each with different functions, and it is nourished by a blood supply that is unique in the body. Knowledge of liver physiology and anatomy not only lends insight as to how the liver functions but also provides the underpinnings for understanding how hepatotoxicants cause liver dysfunction. Therefore, our journey begins with an overview of liver anatomy and physiology. Next, the repertoire of hepatic responses to toxic insult and the various ways of classifying and monitoring liver injury are discussed. Chemical-induced liver injury is typically initiated by one or more critical events, such as formation of a toxic metabolite, which trigger intracellular responses that can progress to dysfunction or death of hepatic parenchymal cells (i.e., HPCs, hepatocytes). These intrahepatocellular events can in turn prompt secondary events involving activation of nonparenchymal cells that magnify or attenuate the initial injury. These events typically determine whether injury progresses to liver failure or to repair of damage. Mechanisms by which such intra- and extrahepatocellular events occur will be discussed in the context of examples of specific chemicals that cause liver injury. Finally, environmental and genetic factors that influence risk of hepatotoxicity from chemical exposure and how these factors determine individual sensitivity to intoxication will be considered.
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In this chapter, reference is made to appropriate research and review articles that expand on specific topics that are discussed. To avoid unnecessary duplication, the reader is also referred to other chapters in this volume that treat liver-related topics such as biotransformation of chemicals (Chap. 6), hepatocarcinogenesis (Chap. 8), the importance of exposure and dose–response (Chap. 3), immune cells and mediators (Chap. 12), and pathways to cell death (Chap. 3...