Chapter 13: Toxic Responses of the Liver

Introduction

The liver is the main organ where exogenous chemicals are metabolized and eventually excreted. As a consequence, liver cells are exposed to significant concentrations of these chemicals, which can result in liver dysfunction, cell injury, and even organ failure. If an industrial chemical, for example carbon tetrachloride, bromobenzene, or vinyl chloride, is identified as a hepatotoxicant, the use of the chemical may be restricted, the exposure may be minimized by mandating protective clothing and respirators, and attempts are made to replace it with a safer alternative. In the pharmaceutical industry, adverse effects on the liver are one of the most frequently cited reasons for discontinuing the development of drug candidates. In addition, hepatotoxicity recognized during the postmarketing phase is one of the main causes for withdrawing drugs from the market (Temple and Himmel, 2002). Troglitazone (Rezulin^®), a new antidiabetic drug, was removed from the market after close to 100 of the 1.9 million patients treated with the drug suffered from liver failure (Chojkier, 2005). Thus, predictable and idiosyncratic hepatotoxicities severely restrict drug discovery efforts and drug development (Lee and Senior, 2005). Furthermore, the increasing popularity of herbal medicines, which are generally plant extracts, enhances the incidence of drug-induced liver injury and liver failure (Stickel et al., 2011). Since these medicines are mixtures of sometimes hundreds of compounds, it remains a difficult task to identify the causative chemical and the mechanism of injury (Lee and Senior, 2005). Basic science and clinical aspects of drug- and chemical-induced liver injury were discussed in detail in several monographs and reviews (Zimmerman, 1999; Jaeschke et al., 2002, 2012a, b; Kaplowitz and DeLeve, 2002; Boyer et al., 2006b; Grattagliano et al., 2009; Roth and Ganey, 2010; Jones et al., 2010).

Given the unprecedented speed of drug discovery and the increasing demand and use of “natural products” as food supplements and medicine, the early identification of hepatotoxicants remains a formidable challenge for the future. The liver, with its multiple cell types and numerous functions, can respond in many different ways to acute and chronic insults. To recognize potential liver cell dysfunction and injury, it is necessary to have a general knowledge of basic liver functions, the structural organization of the liver, the processes involved in the excretory functions of the liver, and mechanisms of cell and organ injury. Each of these aspects can contribute to mechanisms of drug- and chemical-induced hepatotoxicities.

Liver Physiology

Hepatic Functions

The liver's strategic location between the intestinal tract and the rest ...