Bromobenzene toxicity

It has been suggested that the enterhepatobiliary cycle plays a role in the hepatic necrosis observed in bromobenzene toxicity. This is supported by the experimental findings that bromobenzene-induced hepatic necrosis can be prevented by the administration of cholestyramine. 

Wang BH, Zuzel KA, Rahman K, et al. Treatment with aged garlic extract protects against bromobenzene toxicity to precision cut rat liver slices. Toxicology 1999 132 215-25. 

Historically the first cases attributing chloroform to liver toxicity were described in 1887, 1889 and 1904. The role of carbon tetrachloride and liver injury has been originally described in 1967 and 1973. In general, the understanding of hepatotoxicity is extremely complex, and the reader is referred to the outstanding text by Hyman J. Zimmerman. A typical example of how metabolism and toxicity of a water takes place is the aromatic chemical such as benzene attached to bromine. The effect on the liver has been originally studied by Mitchell in 1975 who have shown that a change in the rate of the metabolism of this compound is required to create its toxic products. While bromobenzene and carbon tetrachloride share a similar place of metabolism in the liver, the toxicity of bromobenzene and carbon tetrachloride are different, since the bromobenzene toxicity is related to the metabolic capacity of the liver, while that of carbon tetrachloride is not. 

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. 

Schnellman, R.G. and Mandel, L.J. (1986). Cellular toxicity of bromobenzene and bromo-benzene metabolites to rabbit proximal tubules The role and mechanism of 2-bromohy-droquinone. J. Pharmacol. Exp. Then 237 456 161. 

J. Brodeur, R. Goyal, Effect of a Cysteine Prodrug, L-2-Oxothiazobdine-4-carboxybc Acid, on the Metabobsm and Toxicity of Bromobenzene An Acute Study , Can. J. Physiol. Pharmacol. 1987, 65, 816 - 822. 

Toxicity can occur because, unfortunately, some metabolites are, unlike benzoic acid, more toxic than the chemical that enters the body. Enzymes can cause certain changes in molecular arrangements that introduce groupings of atoms that can interact with components of cells in highly damaging ways. The industrial chemical bromobenzene can be converted in the liver to a metabolite called bromobenzene epoxide, as depicted in the diagram. 

The epoxide molecule is very active and can bind chemically to certain liver cell molecules and cause damage and even death to the cell (Path A). But an alternative reaction path (Path B) can also operate. If the amount of bromo benzene that enters the cell is low enough, Path B (which actually creates several metabolites) dominates and little or no cell damage occurs because the metabolic products are relatively non-toxic and are readily excreted from the body. But as soon as the capacity of the cell to detoxify is overcome because of excessive concentrations of bromobenzene, the dangerous Path A begins to operate and cell damage ensues. 

The epoxide of bromobenzene is one such toxic intermediate, and this example is discussed in more detail in chapter 7. In the case of some carcinogenic poly cyclic hydrocarbons such as benzo[a]pyrene, however, it seems that the dihydrodiol products are in turn further metabolized to epoxide-diols, the ultimate carcinogens (see chap. 7, Figs. 7.2 and 7.3). 

Another example of a glutathione conjugate responsible for toxicity is the industrial chemical hexachlorobutadiene discussed in chapter 7. The diglutathione conjugate of bromobenzene is believed to be involved in the nephrotoxicity after further metabolic activation (chap. 7, Fig. 7.31). 

The converse is true of drugs requiring metabolic activation for toxicity. For example, paracetamol is less hepatotoxic to newborn than to adult mice, as less is metabolically activated in the neonate. This is due to the lower levels of cytochromes P-450 in neonatal liver (Fig. 5.30). Also involved in this is the hepatic level of glutathione, which is required for detoxication. Although levels of this tripeptide are reduced at birth, development is sufficiently in advance of cytochrome P-450 levels to ensure adequate detoxication (Fig. 5.30). The same effect has been observed with the hepatotoxin bromobenzene. (For further details of paracetamol and bromobenzene see chap. 7.) Similarly, carbon tetrachloride is not hepatotoxic in newborn rats as metabolic activation is required for this toxic effect, and the metabolic capability is low in the neonatal rat. 

Bromobenzene is a toxic industrial solvent that causes centrilobular hepatic necrosis in experimental animals. It may also cause renal damage and bronchiolar necrosis. The study of the mechanism underlying the hepa to toxicity of bromobenzene has been of particular importance in leading to a greater understanding of the role of GSH and metabolic activation in toxicity. 

The mechanism of hepatotoxicity is therefore currently unclear. It has been suggested that lipid peroxidation is responsible rather than covalent binding to protein. Arylation of other low molecular weight nucleophiles such as coenzyme A and pyridine nucleotides also occurs and may be involved in the toxicity. Bromobenzene is known to cause the inhibition or inactivation of enzymes containing SH groups. It also causes increased breakdown of phospholipids and inhibits enzymes involved in phospholipid synthesis. Arylation of sites on... 

Bromobenzene is also nephrotoxic but because of different mechanisms. This toxicity is due to the production of reactive GSH conjugates. This is discussed in more detail later in this chapter. 

Thus, bromobenzene hepato toxicity is probably the result of metabolic activation to a reactive metabolite, which covalently binds to protein and other macromolecules and other cellular molecules. It may also stimulate lipid peroxidation, and biochemical effects, such as the inhibition of SH-containing enzymes, may also play a part. 

The proposed activation of acetylhydrazine involves N-hydroxylation, followed by loss of water to yield acetyldiazine, an intermediate that would fragment to yield acetyl radical or acetyl carbonium ion (Fig. 7.24). GSH was not depleted by hepatotoxic doses of acetylhydrazine, indicating that unlike bromobenzene or paracetamol toxicity, it does not have a direct protective role. 

Bromobenzene is toxic to the liver. It produces two reactive metabolites. Which one is thought to be responsible for the hepa to toxicity and why Are there any routes of detoxication, and if so, what are they What effect would treating with the enzyme inducer 3-methylcholanthrene have ... 

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. 

Bromobenzene is a toxic industrial solvent that is known to produce centrilobular hepatic necrosis through the formation of reactive epoxides. Figure 14.6 summarizes... 

Studies of liver toxicity caused by bromobenzene, acetaminophen, and other compounds have led to some important observations concerning tissue damage ... 

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