PRINCIPLES OF TOXICOLOGY

114 HEPATOTOXICITY: TOXIC EFFECTS ON THE LIVER
from the hepatic artery and portal veins, traverses the lobule through hepatic sinusoids, and exits
through 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 as
occupying 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 proposed
a 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 small
vessels radiating from the portal triad is zone 1. Cells in zone 1 are first to receive blood through the
sinusoids. Blood then travels past cells in zones 2 and 3 before reaching the hepatic venule. As can be
seen in Figure 5.3, zone 3 is roughly analogous to the centrilobular region of the classic lobule, since
it is closest to the central vein. Zone 3 cells from adjacent acini form a star-shaped pattern around this
vessel. Zone 1 cells surround the terminal afferent branches of the portal vein and hepatic artery, and
are 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 has
been provided by Lamers and colleagues (1989) (Figure 5.3, right). Based on histopathologic and
immunohistochemical studies, they propose that zone 3 should be viewed as a circular, rather than
star-shaped, region surrounding the central vein. Zone 1 cells surround the portal tracts, and zone 1
cells from adjacent acini merge to form a reticular pattern. As with the Rappaport (1979) model, cells
in zone 3 may be described as centrilobular (matching closely the classic lobular terminology), cells
in 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 blood
supply 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 are
reflected in differing morphology and enzymatic content between cells in zones 1 and 3. Consistent
with 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 acid
oxidation. Glucose formation from gluconeogenesis and from breakdown of glycogen predominate in
zone 1 cells, and most secretion of bile acids occurs here. On the other hand, most forms of the
biotransformation enzyme cytochrome P450 are found in highest concentrations in zone 3 cells. As
the site of biotransformation for most drugs and chemicals, zone 3 cells have greatest responsibility
for their detoxification. This also means that zone 3 cells are often the primary targets for chemicals
that 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.