PRINCIPLES OF TOXICOLOGY - Biology East Borneo

114 HEPATOTOXICITY: TOXIC EFFECTS ON THE LIVERfrom the hepatic artery and portal veins, traverses the lobule through hepatic sinusoids, and exitsthrough a hepatic venule. In the typical lobule view, cells near the portal vein are termed periportal,while those near the hepatic venule are termed perivenular. The hepatic venule is visualized asoccupying the center of the lobule, and cells surrounding the venule are sometimes termed centrilobular,while those farther away, near the portal triad, are called peripheral lobular. Rappaport proposeda different view of hepatic anatomy in which the basic anatomical unit is called the simple liver acinus.In this view (Figure 5.3, left), cells within the acinus are divided into zones. The area adjacent to smallvessels radiating from the portal triad is zone 1. Cells in zone 1 are first to receive blood through thesinusoids. Blood then travels past cells in zones 2 and 3 before reaching the hepatic venule. As can beseen in Figure 5.3, zone 3 is roughly analogous to the centrilobular region of the classic lobule, sinceit is closest to the central vein. Zone 3 cells from adjacent acini form a star-shaped pattern around thisvessel. Zone 1 cells surround the terminal afferent branches of the portal vein and hepatic artery, andare often stated as occupying the periportal region, while cells between zones 1 and 3 (i.e., in zone 2)are said to occupy the midzonal region. A modification of the typical lobule and acinar models hasbeen provided by Lamers and colleagues (1989) (Figure 5.3, right). Based on histopathologic andimmunohistochemical studies, they propose that zone 3 should be viewed as a circular, rather thanstar-shaped, region surrounding the central vein. Zone 1 cells surround the portal tracts, and zone 1cells from adjacent acini merge to form a reticular pattern. As with the Rappaport (1979) model, cellsin zone 3 may be described as centrilobular (matching closely the classic lobular terminology), cellsin zone 1 as periportal, and the cells in zone 2 in between are called midzonal.Each of these viewpoints has in common a recognition that the cells closest to the arterial bloodsupply receive the highest concentrations of oxygen and nutrients. As blood traverses the lobule,concentrations of oxygen and nutrients diminish. Differences in oxygen tension and nutrient levels arereflected in differing morphology and enzymatic content between cells in zones 1 and 3. Consistentwith their greater access to oxygen, hepatocytes in zone 1 are better adapted to aerobic metabolism.They have greater respiratory activity, greater amino acid utilization, and higher levels of fatty acidoxidation. Glucose formation from gluconeogenesis and from breakdown of glycogen predominate inzone 1 cells, and most secretion of bile acids occurs here. On the other hand, most forms of thebiotransformation enzyme cytochrome P450 are found in highest concentrations in zone 3 cells. Asthe site of biotransformation for most drugs and chemicals, zone 3 cells have greatest responsibilityfor their detoxification. This also means that zone 3 cells are often the primary targets for chemicalsthat are bioactivated by these enzymes to toxic metabolites in the liver.Figure 5.3 Alternative views of the liver acinus. Reproduced with permission from Lamers et al., 1989.