Liver necrosis bromobenzene

Bromobenzene, similarly to acetaminophen, is considered as model compound in liver necrosis (refs. 9-11, 20, 21). After the administration of these compounds, a considerable decrease in GSH levels, an increase in GTP activity in the serum and, histopathologically, necrosis of hepatocytes are observed. 

Zampaglione N, JoIIow DJ, Mitchell JR, et al. Role of detoxifying enzymes in bromobenzene-induced liver necrosis. J Pharmacol Exp Ther 1973 187(1 ) 218-227. 

A pattern of liver necrosis similar to that caused by bromobenzene is observed in patients who ingest massive doses of acetaminophen (Table 16.2). This toxic reaction also has been produced experimentally in mice and rats and is thought to occur in two phases. An initial metabolic phase in which acetaminophen is converted to a reactive iminoquinone metabolite is followed by an oxidation phase in which an abrupt increase in mitochondrial permeability, termed mitochondrial permeability transition (MPT), leads to the release of superoxide and the generation of oxidizing nitrogen and peroxide species that result in hepatocellular necrosis (13, 14). 

Casini AF, Pompella A, Comporti M (1984) Glutathione depletion, lipid peroxidation, and liver necrosis following bromobenzene and iodobenzene intoxication. Toxicol Pathol 12 295-299... 

Jewell H, Maggs JL, Harrison AC et al (1995) Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine. Xenobiotica 25 199-217 follow DJ, Mitchell JR, Zampaglione N et al (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3, 4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11 151-169... 

J. R. Bromobenzene induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic intermediate. Pharmacology, 1974, 11,... 

For example, consider bromobenzene as a cause of liver necrosis. Identification of metabolites formed from bromobenzene and their relationship to observed necrosis has been investigated, and a reactive intermediate of bromobenzene was implicated. Pretreatment with inducers and inhibitors of bromobenzene metabolites were used experimentally. This is represented by a general relationship shown in Figure 1 ( 3). In the case of bromobenzene, the reactive intermediate is 3,4-bromobenzene oxide. These studies require the efforts of biochemists and toxicologists, and the interdisciplinary nature of the investigation is readily seen. The joint effort promotes understanding. 

Hepatotoxins Agents that produce liver damage, such as liver necrosis, fatty liver, cirrhosis, and carcinogenesis. Examples of hepatotoxins include carbon tetrachloride, aflatoxins, phosphorus, ethanol, bromobenzene, and nitrosamines. 

Yellow phosphorus was the first identified liver toxin. It causes accumulation of lipids in the liver. Several liver toxins such as chloroform, carbon tetrachloride, and bromobenzene have since been identified. I he forms of acute liver toxicity are accumulation of lipids in the liver, hepartxiellular necrosis, iii-trahepatic cholestasis, and a disease state that resembles viral hepatitis. The types of chrome hepatotoxicity are cirrhosis and liver cancer. 

The metabolite of bromobenzene that is believed to be responsible for the hepatic necrosis is bromobenzene 3,4-oxide. This reacts with liver cell protein, which causes cell death. The reactive metabolite can be detoxified by conjugation with glutathione or be detoxified by metabolism to a dihydrodiol by epoxide hydrolase. Pretreatment of animals with the enzyme inducer 3-methylcholanthrene decreases the toxicity. This is because it increases metabolism to the 2,3-oxide. This reactive metabolite is not as toxic as the 3,4-bromobenzene oxide readily undergoing rearrangement to 2-bromophenol. 3-Methylcholanthrene also induces epoxide hydrolase and so increases detoxication. 

Fig. 12. Paraffin sections of rat liver, periodic acid Schiff stain X22. A, normal liver of control animal killed 24 h after injection of 1 ml of seasame oil i.p. B, extensive centrolobular necrosis of parenchymal cells in rat killed 24 h after administration of high dose of bromobenzene (0.2 ml i.p.). C, Liver 24 h after lower dose of bromobenzene (0.03 ml i.p.). The centrolobular areas exhibit some small patches of round cell infiltration and decreased glycogen staining in the cytoplasm after hepatocytes but little necrosis. D, Extensive centrolobular necrosis after administration of the same low dose of bromobenzene (0.03 ml i.p.) to a rat treated with pheno-barbital (20 mg/kg) for 3 days in order to induce hepatic microsomal enzymes. After Brodie et al...

Aromatic chemicals are metabolized into unstable arene-oxides, which, as epoxides, are comparable to potentially equivalent electrophilic carbocations. These metabolites react easily with thiol groups derived from proteins, leading, for example, to hepatotoxicity. Bromobenzene (Fig. 32.10) is oxidized into a 3-4 epoxide, which does not exhibit mutagenic or carcinogenic activity, but reacts nonenzymatically with liver proteins and produces hepatic necrosis. A secondary P450-catalysed oxidation to hydroquinone... 

Liver halogenated hydrocarbons (e.g., caib[Pg.1319]

The toxic effects of hydrocarbons are well established. Injection of 150 mg/kg of bromobenzene into rats produces acute centrolobulm- hepatic necrosis within 48 hours (Koch-Weser el al., 1952). The toxieitj is related to the general nutiitional state, ilethionine and cj stine, or a high protein diet, effectively combat the effects of the hydrocarbons. Koch-Weser suggests the liver damage is due to removal of cysteine and methionine, since p-dibromobenzene and p-bromochlorobenzene, which do not form mercapturic acids, do not cause hepatic lesions while w-chloro-... 

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