It has been suggested that the enterohepatic circulation plays a role in the hepatic necrosis observed in bromobenzene poisoning. This is supported by experimental results that bromobenzene-induced hepatic necrosis can be prevented by administration of cholestyramine.
After ingestion, bromobenzene is readily absorbed from the gastrointestinal tract. Bromobenzene is also absorbed into the lungs after inhalation. Bromobenzene and its metabolites are distributed throughout the body, with highest concentrations in adipose tissue shortly after absorption.
Bromobenzene is initially converted to epoxide derivatives by CYP isoenzymes, specifically cytochrome P-450. Subsequently, the major metabolic pathway in rat liver is the conjugation of 3,4-epoxide derivatives to glutathione (GSH) (spontaneously or via glutathione-S-transferase), followed by thiouric acid form excretion. Approximately 70% of the bromobenzene was recovered as thiouric acid within 8 hours of ingestion by rats. Catechol, quinone, phenol, and dihydrodiol (or bromophenol) metabolites were also detected in the urinary excretions of animals. While the liver is capable of producing all of the various metabolites of bromobenzene, lung and kidney tissues have been shown to produce limited amounts of certain metabolites.
Bromobenzene, an industrial solvent also used as a motor oil additive, causes hepatotoxicity after biotransformation in the liver to its reactive toxic metabolite bromobenzene 3,4-epoxide by CYP450 enzymes. After GSH depletion, in addition to oxidative stress and lipid peroxidation, reactive metabolites are covalently bound to cellular macromolecules, ultimately leading to centrilobular hepatocyte necrosis (Lau and Monks, 1988). Hepatic Mrp1 and Mrp3 mRNA levels were higher in bromobenzene-treated rats (Heijne et al., 2004). Increased Mrp3 gene expression was also observed in the liver of rats repeatedly treated with bromobenzene. Repeated exposure to bromobenzene also resulted in tolerance to hepatotoxicity, suggesting that increased Mrp3 may contribute to this acquired resistance.
Bromobenzene is an industrial solvent used in the synthesis and production of the synthetic intermediate phenylmagnesium bromide as an engine oil additive and crystallization solvent, and is a neurotoxic and hepatotoxic substance (El-Sharaky et al., 2009).