PRINCIPLES OF TOXICOLOGY - Biology East Borneo

5.2 TYPES OF LIVER INJURY 119Examples include lead nitrate and phenobarbital. When exposure or treatment with these agents hasended, the liver will return to its normal size. During this phase, the number of apoptotic cells isincreased, reflecting an effort by the liver to reduce its size, in part by eliminating some of its cells.Drugs and chemicals can produce hepatocellular degeneration and death by many possiblemechanisms. For some hepatotoxicants, the mechanism of toxicity is reasonably well established. Forexample, galactosamine is thought to cause cell death by depleting uridine triphosphate, which isessential for synthesis of membrane glycoproteins. For most hepatotoxicants, however, key biochemicaleffects responsible for hepatocellular necrosis remain uncertain. The search for a broadly applicablemechanism of hepatotoxicity has yielded several candidates:Lipid Peroxidation Many hepatotoxicants generate free radicals in the liver. In some cases, such ascarbon tetrachloride, the free radicals are breakdown products of the chemical generated by itscytochrome P450-mediated metabolism in the liver. In other cases, the chemical causes a disruptionin oxidative metabolism within the cell, leading to the generation of reactive oxygen species. Animportant potential consequence of free-radical formation is the occurrence of lipid peroxidation inmembranes within the cell. Lipid peroxidation occurs when free radicals attack the unsaturated bondsof fatty acids, particularly those in phospholipids. The free radical reacts with the fatty acid carbonchain, abstracting a hydrogen. This causes a fatty acid carbon to become a radical, with rearrangementof double bonds in the fatty acid carbon chain. This carbon radical in the fatty acid reacts with oxygenin a series of steps to produce a lipid hydroperoxide and a lipid radical that can then react with anotherfatty acid carbon. The peroxidation of the lipid becomes a chain reaction, resulting in fragmentationand destruction of the lipid. Because of the importance of phospholipids in membrane structure, theprincipal consequence of lipid peroxidation for the cell is loss of membrane function. The reactiveproducts generated by lipid peroxidation can interact with other components of the cell as well, andthis also could contribute to toxicity.The list of chemicals that produce lipid peroxidation as part of their hepatotoxic effects is extensive,and includes halogenated hydrocarbons (e.g., carbon tetrachloride, chloroform, bromobenzene,tetrachloroethene), alcohols (e.g., ethanol, isopropanol), hydroperoxides (e.g., tert-butylhydroperoxide),herbicides (e.g., paraquat), and a variety of other compounds (e.g., acrylonitrile, cadmium,cocaine, iodoacetamide, chloroacetamide, sodium vanadate). Consequently, it is an attractive commonmechanism of hepatotoxicity. There is some question, however, as to whether it is the most importantmechanism of toxicity for these chemicals. For some of these hepatotoxic compounds, experimentshave been conducted in which lipid peroxidation was blocked by concomitant-treatment with anantioxidant. In many cases, hepatotoxicity still occurred. This argues that for at least some agents, lipidperoxidation may contribute to their hepatotoxicity, but is not sufficient to explain all of their toxiceffects on the liver.Irreversible Binding to Macromolecules Most of the conventional hepatotoxicants must be metabolizedin order to produce liver toxicity, producing one or more chemically reactive metabolites. Thesereactive metabolites bind irreversibly to cellular macromolecules—primarily proteins, but in somecases also lipids and DNA. This binding precedes most manifestations of toxicity, and the extent ofbinding often correlates well with toxicity. In fact, histopathology studies with some of these chemicalshave found that only cells with detectable reactive metabolite binding undergo necrosis. Examples ofhepatotoxic chemicals that produce reactive metabolites include acetaminophen, bromobenzene,carbon tetrachloride, chloroform, cocaine, and trichloroethylene.It is certainly plausible that irreversible binding of a toxicant to a critical protein or othermacromolecule in the cell could lead to loss of its function, and the fact that binding precedes most,if not all, toxic responses in the cell make it a logical initiating event. However, demonstrating preciselyhow irreversible binding causes cell death has been extremely challenging. Several studies have beenconducted attempting to identify the macromolecular targets for binding and to determine whether thisbinding results in an effect that could lead to cell death. Acetaminophen, in particular, has been studiedin this regard. While several proteins bound by the acetaminophen reactive metabolite, N-acetyl-p-