PRINCIPLES OF TOXICOLOGY

TABLE 5.2 Drugs and Chemicals that Produce Fatty Liver
Antimony Ethyl chloride
Barium salts Hydrazine
Borates Methyl bromide
Carbon disulfide Orotic acid
Chromates Puromycin
Dichloroethylene Safrole
Dimethylhydrazine Tetracycline
Ethanol Thallium compounds
Ethionine Uranium compounds
Ethyl bromide White phosphorus
5.2 TYPES OF LIVER INJURY 121
tetracycline, valproic acid, salicylates, aflatoxin, dimethylformamide, and some of the antiviral
nucleoside analogs used to treat HIV. It is also associated with Reye’s syndrome and fatty liver of
pregnancy. Macrovesicular steatosis has been associated with antimony, barium salts, carbon disulfide,
dichloroethylene, ethanol, hydrazine, methyl and ethyl bromide, thallium, and uranium compounds.
There are several potential chemical effects that can give rise to accumulation of lipids in the cell.
These include:
1. Inhibition of Lipoprotein Synthesis. A number of chemicals are capable of inhibiting synthesis
of the protein moiety needed for synthesis of lipoproteins in the liver. These include carbon
tetrachloride, ethionine, and puromycin.
2. Decreased Conjugation of Triglycerides with Lipoproteins. Another critical step in lipoprotein
synthesis is conjugation of the protein moiety with triglyceride. Carbon tetrachloride, for
example, can interfere with this step.
3. Interference with Very-Low-Density Lipoprotein (VLDL) Transfer. Inhibition of transfer of
VLDL out of the cell results in its accumulation. Tetracycline is an example of an agent that
interferes with this transfer.
4. Impaired Oxidation of Lipids by Mitochondria. Oxidation of nonesterified fatty acids is an
important aspect of their hepatocellular metabolism, and decreased oxidation can contribute
to their accumulation within the cell. Carbon tetrachloride, ethionine, and white phosphorus
have been shown to inhibit this oxidation.
5. Increased Synthesis of Fatty Acids. The liver is capable of synthesizing fatty acids from
acetyl-CoA (coenzyme A), and increased fatty acid synthesis can increase the lipid burden of
the cells. Ethanol is an example of a chemical that produces this effect.
Other possible mechanisms might contribute to fatty liver, such as increased uptake of lipids from
the blood by the liver, but the role of these processes in drug- or chemical-induced steatosis is less
clear. The mechanisms listed above are not mutually exclusive. Indeed, it is likely that many of the
chemicals that produce steatosis do so by producing more than one of these effects.
Fatty liver may occur by itself, or in conjunction with hepatocellular necrosis. Many chemicals
produce a lesion that consists of both effects. Examples include: aflatoxins, amanitin, arsenic compounds,
bromobenzene, carbon tetrachloride, chloroform, dimethylnitrosamine, dinitrotoluene, DDT,
dichloropropane, naphthalene, pyrrolizidine alkaloids, and tetrachloroethane. Drug- or chemical-induced
steatosis is reversible when exposure to the agent is stopped.
Phospholipidosis is a special form of steatosis. It results from accumulation of phospholipids in
the hepatocyte, and can be caused by some drugs as well as by inborn errors in phospholipid
metabolism. Liver sections from patients with phospholipidosis reveal enlarged hepatocytes with