Hepatic toxicity biomarkers

The liver is the largest internal organ in the human body and it is the main organ for the metabolism and detoxification of drugs and environmental chemicals (Klaassen, 2007). Other main functions of the liver include glucose storage and synthesis, decomposition of red blood cells, plasma protein synthesis, hormone production, and bile formation. Anatomically, the liver lies slightly below the diaphragm and anterior to the stomach, a position that facilitates maintaining metabolic homeostasis of the body. Two distinct blood supplies feed the liver: the portal vein and the hepatic artery. The portal vein carries blood containing digested nutrients from the gastrointestinal tract, spleen and pancreas, while the hepatic artery carries oxygenated blood from the lungs. The human liver consists of four lobes, and each lobe is made up of many lobules, which is defined at the microscopic scale. The classical lobule is a hexagonalshaped unit centered around a central vein. In each functional unit, blood enters the lobules from the portal vein and hepatic artery, and then flows down past the cords of hepatocytes. The lobule is divided into three regions (Figure 13.1): (1) periportal (Zone 1) is the closest to the entering blood supply with the highest oxygen tension; (2) centrilobular (Zone 3) abuts the central vein and has the poorest oxygenation; and (3) midzonal (Zone 2) is intermediate. Due to the blood flows from the stomach and intestine, the liver is the first internal organ to encounter a number of insults including ingested metals, drugs, and environmental toxicants (Klaassen, 2007). As a consequence, liver cells are exposed to significant concentrations of these chemicals, and liver functions can be adversely affected by the acute or chronic exposure. For example, acetaminophen (APAP) is a widely used over-the-counter analgesic and antipyretic in the United States (Hinson et al., 2010). When used at recommended therapeutic doses, APAP is rarely associated with liver injury. Unfortunately, APAP can cause fatal acute liver failure when therapeutic doses are exceeded due to the production of a highly reactive hepatotoxic metabolite in the liver (Lee, 2004). Since the liver is often exposed to the highest concentrations of orally consumed drugs, it is not surprising that the liver is often the target organ with ensuing drug-induced liver injury (DILI). DILI is a major challenge for the pharmaceutical industry and public health, since DILI is a common cause of drug development termination, drug restrictions, and post-marketing drug withdrawal (Kaplowitz, 2005). Currently, more than 1000 drugs have been reported to be associated with DILI (Shi et al., 2010). In addition, the increasing popularity of dietary supplements (DS) may contribute to the high incidence of DILI since some DS have various toxicological effects or alter the toxicity of concomitantly administered drugs (Abebe, 2002; Estes et al., 2003; Zhou et al., 2007; Dara et al., 2008; Salminen et al., 2012). Typically, DILI has been classified in terms of the clinical liver disease which is hepatocellular, cholestatic, or mixed hepatocellular/cholestatic. Hepatocellular often involves cellular damage of the hepatocytes such as the centrilobular necrosis caused by APAP. This type of damage is often associated with elevated serum alanine aminotransferase (ALT) levels due to leakage from damaged hepatocytes. Cholestatic injury often involves damage to some part of the bile processing or excretion apparatus, resulting in impaired bile processing or excretion.