PRINCIPLES OF TOXICOLOGY

116 HEPATOTOXICITY: TOXIC EFFECTS ON THE LIVER
system. They are capable of releasing reactive oxygen species and cytokines, and play an important
role in inflammatory responses in the liver. The liver also contains Ito cells (also termed fat-storing
cells, parasinusoidal cells, or stellate cells) which lie between parenchymal and endothelial cells. These
cells appear to be important in producing collagen and in vitamin A storage and metabolism.
5.2 TYPES OF LIVER INJURY
All chemicals do not produce the same type of liver injury. Rather, the type of lesion or effect observed
is dependent on the chemical involved, the dose, and the duration of exposure. Some types of injury
are the result of acute toxicity to the liver, while others appear only after chronic exposure or treatment.
Basic types of liver injury include the anomalies described in the following paragraphs.
Hepatocellular Degeneration and Death
Many hepatotoxicants are capable of injuring liver cells directly, leading to cellular degeneration and
death. A variety of organelles and structures within the liver cell can be affected by chemicals. Principal
targets include the following:
1. Mitochondria. These organelles are important for energy metabolism and synthesis of ATP.
They also accumulate and release calcium, and play an important role in calcium homeostasis within
the cell. When mitochondria become damaged, they often lose the ability to regulate solute and water
balance, and undergo swelling that can be observed microscopically. Mitochondrial membranes can
become distorted or rupture, and the density of the mitochondrial matrix is altered. Examples of
chemicals that show damage to hepatic mitochondria include carbon tetrachloride, cocaine, dichloroethylene,
ethionine, hydrazine, and phosphorus.
2. Plasma Membrane. The plasma membrane surrounds the hepatocyte and is critically important
in maintaining the ion balance between the cytoplasm and the external environment. This ion balance
can be disrupted by damage to plasma membrane ion pumps, or by loss of membrane integrity causing
ions to leak in or out of the cell following their concentration gradients. Loss of ionic control can cause
a net movement of water into the cell, resulting in cell swelling. Blisters or “blebs” in the plasma
membrane may also occur in response to chemical toxicants. Examples of chemicals that show damage
to plasma membrane include acetaminophen, ethanol, mercurials, and phalloidin.
3. Endoplasmic Reticulum. The endoplasmic reticulum is responsible for synthesis of proteins
and phospholipids in the hepatocyte. It is the principal site of biotransformation of foreign chemicals
and, along with the mitochondria, sequesters and releases calcium ions to promote calcium homeostasis.
As discussed in Chapter 3, hepatic biotransformation enzyme activity is substantially increased in
response to treatment or exposure to a variety of chemicals. Many of these enzymes, including
cytochrome P450, are located in the endoplasmic reticulum, which undergoes proliferation as part of
the enzyme induction process. Because the endoplasmic reticulum is the site within the cell of most
oxidative metabolism of foreign (xenobiotic) chemicals, it is also the site where reactive metabolites
from these chemicals are formed. This makes it a logical target for toxicity for chemicals that produce
injury through this mechanism. Morphologically, damage to the endoplasmic reticulum often appears
in the form of dilation. Examples of chemicals that show damage to endoplasmic reticulum include
acetaminophen, bromobenzene, carbon tetrachloride, and cocaine.
4. Nucleus. There are several ways in which the nuclei can be damaged by chemical toxicants.
Some chemicals or their metabolites can bind to DNA, producing mutations (see Chapter 12). These
mutations can alter critical functions of the cell leading to cell death, or can contribute to malignant
transformation of the cell to produce cancer. Some chemicals appear to cause activation of endonucleases,
enzymes located in the nucleus that digest chromatin material. This leads to uncontrolled
digestion of the cell’s DNA—obviously not conducive to normal cell functioning. Some chemicals