Toxic Responses

Toxic Responses
THE LIVER

The liver is often the first major metabolizing organ that an ingested toxicant encounters, and
it has very high metabolic activity. The major function of the liver is to metabolize, store, and
release nutrients, that is, to maintain nutrient homeostasis. When blood levels of nutrient molecules
are high, the liver can convert them to glycogen and fats and store them. When blood levels of
nutrients are low, the liver can convert some amino acids, pyruvate, and lactate to glucose, which
is released to blood. It uses amino acids to synthesize proteins that are released to blood, including
albumin, clotting factors, and transport proteins. The liver is the major site of fat metabolism and
releases fat to blood as needed. It produces bile, which acts to emulsify fats in the small intestine.
Materials enter and leave the liver as blood in arteries and veins. Nutrients, drugs, and ingested
xenobiotics absorbed from the small intestine go directly to the liver through the portal vein. The
liver has another mechanism for excretion in the form of bile discharged back to the intestines.
Bile discharge is a major route of elimination of xenobiotic compounds and their metabolites.
Insofar as toxicological chemistry is concerned, the major function of the liver is to metabolize
xenobiotic substances through phase I and phase II reactions. Because of this function, the liver is
a crucial organ in the study of toxicological chemistry. Since it processes xenobiotic chemicals,
the liver is often the organ that is damaged by such chemicals and their metabolites. Recall from
Chapter 8 that the livers of genetically susceptible individuals can be damaged by therapeutic doses
of some drugs, such as those shown in Figure 8.5. Other xenobiotics ingested accidentally can
damage the liver. Toxic effects to the liver are studied under the topic of hepatotoxicity, and substances that are toxic to the liver are called hepatotoxins . Much is known about hepatotoxicity from the many
cases of liver toxicity that are a manifestation of chronic alcoholism. Liver injury from excessive
alcohol ingestion initially hampers the ability of the organ to remove lipids, resulting in their
accumulation in the liver (fatty liver). The liver eventually loses its ability to perform its metabolic
functions and accumulates scar tissue, a condition known as cirrhosis. Inability to synthesize clotting
factors can cause fatal hemorrhage in the liver.
A wide range of substances can cause hepatotoxicity. Even an essential vitamin, vitamin A,

is hepatotoxic in overdoses, a fact that should be kept in mind by health food fans who drink large

amounts of carrot juice. Other hepatotoxins include toxins in hormones, tea (germander), and

drinking water infested with the photosynthetic cyanobacteria Microcystis aeruginosa . Each year

people are killed by eating toxic mushrooms, especially the appropriately named “death cap” mushroom,

Amanita phalloides . This fungus produces a mycotoxin consisting of seven amino acid residues, a heptapeptide called phalloidin. A great deal of information about hepatotoxicity has resulted from observed effects of pharmaceuticals, a number of which have been discontinued because of their damaging effects to the liver. An example of such a hepatotoxic compound tested as a pharmaceutical is fialuridine, which was tested during the mid-1990s as a treatment for viral chronic hepatitis B, a liver disease. Seven of 13 patients in the test developed debilitating hepatotoxicity with severe jaundice, alongbwith lactic acidosis due to accumulation of lactic acid, a metabolic intermediate. The seven patients were given liver transplants, but five of them died.

which was tested during the mid-1990s as a treatment for viral chronic hepatitis B, a liver disease.

Seven of 13 patients in the test developed debilitating hepatotoxicity with severe jaundice, along

with lactic acidosis due to accumulation of lactic acid, a metabolic intermediate. The seven patients

were given liver transplants, but five of them died. Steatosis, commonly known as fatty liver, is a condition in which lipids accumulate in the liver in excess of about 5%. It may result from toxicants that cause an increase in lipid synthesis, a decrease in lipid metabolism, or a decrease in the secretion of lipids as lipoproteins. An example of a substance that causes steatosis is valproic acid, once used as an anticonvulsant:

Other than ethanol, the xenobiotic chemical best known to cause steatosis is carbon tetrachloride,

CCl4 . This compound was once widely used in industry as a solvent, and even in consumer items

as a stain remover. As discussed in some detail in Chapter 16, it is converted by enzymatic action

in the liver to Cl3C· radical, then by reaction with O2 to Cl3COO· radical, which reacts with

unsaturated lipids in the liver to cause fatty liver. The general term hepatitis is used to describe conditions under which the liver becomes inflamed when liver cells that are damaged by a toxic substance, a substance that causes an immune response, or disease die, and their remnants are released to liver tissue. A number of toxicants can cause liver cell death. This is most damaging when it occurs through necrosis of liver cells, in which they rupture and leave remnants in the vicinity, which can lead to inflammation and other adverse effects. Dimethylformamide is a xenobiotic industrial chemical known to cause liver cell death:

A more orderly type of cell death is apoptosis, in which the cells become encapsulated and are

systematically removed from the organ. This essential housekeeping function is accomplished in

the liver by special cells called Kupffer cells. These cells perform phagocytosis , in which a solid

particle, such as a cell remnant or other foreign matter in the liver, becomes encapsulated in a

plasma membrane and incorporated into the Kupffer cell, which is then eliminated. Reduced bile output can result in an accumulation of bilirubin, a dark-colored pigment produced by the breakdown of blood heme. When this product is not discharged at a sufficient rate with bile, it accumulates in skin and eyes, giving the characteristic sickly color of jaundice. Impaired production and excretion of bile is known as canalicular choleostasis . It can be caused by a number of xenobiotic substances, such as chlorpromazine. Reduced bile output can also result from damage to bile ducts. Methylene dianiline used in epoxy resins is known to harm bile ducts.

Cirrhosis , which was mentioned in connection with chronic alcoholism above, is an often fatal

end result of liver damage. It is often the result of repeated exposure to toxic agents, such as occurs

with alcohol imbibed by heavy drinkers. Cirrhosis is characterized by deposition and buildup of

fibrous collagen tissue, which replaces active liver cells and eventually forms barriers in the liver

that prevent it from functioning. Liver tumors have been directly attributed to exposure to some toxicants. Androgens (associated with male sex hormones), aflatoxins (from fungi, see Chapter 19), arsenic, and thorium dioxide (administered as a suspension to many patients between 1920 and 1950 as a radioactive contrast agent for diagnostic purposes) are known to cause liver cancer. Arguably the most clearly documented human carcinogen is vinyl chloride, which has been shown to cause a type of liver tumor called

hemangiosarcoma , which is virtually unobserved except in workers heavily exposed to vinyl chloride.Up until about 1970, workers were exposed to high levels of up to several parts per thousand in air in the polyvinylchloride manufacturing industry. Poisoning was so common that reference was even made to “vinyl chloride disease,”characterized by damage to skin, bones, and liver. It is believed that hemangiosarcoma resulted from the action of the metabolically produced reactive epoxide generated by enzymatic oxidation

of vinyl chloride in the liver:

Stanley E. Manahan