Bromobenzene, liver necrosis metabolites

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). 

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... 

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. 

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. 

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... 

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