PRINCIPLES OF TOXICOLOGY - Biology East Borneo

5.2 TYPES OF LIVER INJURY 121TABLE 5.2 Drugs and Chemicals that Produce Fatty LiverAntimonyBarium saltsBoratesCarbon disulfideChromatesDichloroethyleneDimethylhydrazineEthanolEthionineEthyl bromideEthyl chlorideHydrazineMethyl bromideOrotic acidPuromycinSafroleTetracyclineThallium compoundsUranium compoundsWhite phosphorustetracycline, valproic acid, salicylates, aflatoxin, dimethylformamide, and some of the antiviralnucleoside analogs used to treat HIV. It is also associated with Reye’s syndrome and fatty liver ofpregnancy. 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 synthesisof the protein moiety needed for synthesis of lipoproteins in the liver. These include carbontetrachloride, ethionine, and puromycin.2. Decreased Conjugation of Triglycerides with Lipoproteins. Another critical step in lipoproteinsynthesis is conjugation of the protein moiety with triglyceride. Carbon tetrachloride, forexample, can interfere with this step.3. Interference with Very-Low-Density Lipoprotein (VLDL) Transfer. Inhibition of transfer ofVLDL out of the cell results in its accumulation. Tetracycline is an example of an agent thatinterferes with this transfer.4. Impaired Oxidation of Lipids by Mitochondria. Oxidation of nonesterified fatty acids is animportant aspect of their hepatocellular metabolism, and decreased oxidation can contributeto their accumulation within the cell. Carbon tetrachloride, ethionine, and white phosphorushave been shown to inhibit this oxidation.5. Increased Synthesis of Fatty Acids. The liver is capable of synthesizing fatty acids fromacetyl-CoA (coenzyme A), and increased fatty acid synthesis can increase the lipid burden ofthe 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 fromthe blood by the liver, but the role of these processes in drug- or chemical-induced steatosis is lessclear. The mechanisms listed above are not mutually exclusive. Indeed, it is likely that many of thechemicals 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 chemicalsproduce 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-inducedsteatosis is reversible when exposure to the agent is stopped.Phospholipidosis is a special form of steatosis. It results from accumulation of phospholipids inthe hepatocyte, and can be caused by some drugs as well as by inborn errors in phospholipidmetabolism. Liver sections from patients with phospholipidosis reveal enlarged hepatocytes with