Hepatotoxicity bromobenzene

Heijne WH, Stierum RH, Slijper M, van Bladeren PJ, van Ommen B. Toxicoge-nomics of bromobenzene hepatotoxicity A combined transcriptomics and proteomics approach. Biochem Pharmacol 2003 65(5) 857-75. 

Thus, bromobenzene hepatotoxicity 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. 

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. 

Potential hepatotoxic effects of various brominated benzenes, however, should be considered. Bromobenzene which is a monobrominated compound, is used in various experiments as a model hepatotoxic compound (refs. 9-11). 

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. 

As well as detoxication via reaction with GSH, the reactive 3,4-epoxide can be removed by hydration to form the dihydrodiol, a reaction that is catalyzed by epoxide hydrolase (also known as epoxide hydratase). This enzyme is induced by pretreatment of animals with the polycyclic hydrocarbon 3-methylcholanthrene, as can be seen from the increased excretion of 4-bromophenyldihydrodiol (Table 7.5). This induction of a detoxication pathway offers a partial explanation for the decreased hepatotoxicity of bromobenzene observed in such animals. A further explanation, also apparent from the urinary metabolites, is the induction of the form of cytochrome P-450 that catalyzes the formation of the 2,3-epoxide. This potentially reactive metabolite readily rearranges to 2-bromophenol, and hence there is increased excretion of 2-bromophenol in these pretreated animals (Table 7.5). 

However, administration of primary phenolic metabolites does not cause hepatotoxicity. At least seven GSH conjugates have been identified as metabolites of bromobenzene and its primary phenolic metabolites. 

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... 

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. 

In addition to being hepatotoxic, bromobenzene is also nephrotoxic because of the production of reactive polyphenolic GSH conjugates, covalent binding to protein, and the production of ROS. 2-Bromophenol and 2-bromohydroquinone are both nephrotoxic metabolites of bromobenzene. Quinones are both oxidants and electrophiles, undergoing both one and two electron reduction and reaction with sulfydryl groups such as GSH and... 

Fasting enhances the toxicity of many chemicals. One of the earliest studies of this phenomenon compared the effects of fasting and various diets on chloroform-induced hepatotoxicity. Increased hepatotoxicity in association with fasting occurs with chemicals that are capable of depleting GSH, including carbon tetrachloride, 1,1-dichloroethylene, APAP, bromobenzene, and many others. Because fasting decreases the hepatic concentration of GSH in mice and rats, such a decrease could account for the enhanced toxicity of many of these chemicals in fasted animals. In several instances, as a result of a depletion of GSH in the liver after pretreatment with diethyl maleate, APAP, bromobenzene, carbon tetrachloride, and anthracy-clines, showed increased hepatotoxicity. 

Studies using experimental diabetic animal models have indicated that xenobiotic-induced hepatotoxicity is modulated in diabetes. Hepatotoxicity of several structurally and mechanistically diverse chemicals, such as chloroform, thioacetamide, menadione, nitro-soamines, bromobenzene, and CCI4, is significantly increased in type 1 diabetic rats. It was reported that thioacetamide-induced hepatotoxicity was potentiated in alloxan- or streptozotocin-diabetic rats. Recent studies have confirmed the potentiation of thioacetamide hepatotoxicity in streptozotocin-diabetic rats. Several studies have shown that hepatotoxicity of CCI4 is potentiated in alloxan- or streptozotocin-induced type 1 diabetic rats. 

Heijne WH, Slitt AL, Van Bladeren PJ, Groten JP, Klaassen CD, Stierum RH, Van Ommen B. Bromobenzene-induced hepatotoxicity at the transcriptome level. Toxicol Sci 2004 79(2) 411-22. 

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 seems to target a large group of functionally diverse hepatic proteins, as demonstrated recently in a proteomic analysis. The chemical is oxidized (Figure 33.10) into a 3,4-epoxide, which... 

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

The metabolites 2- and 4- bromophenol can also be metabolized by a further oxidation pathway to yield catechols and quinones, some of which are cytotoxic and potentially hepatotoxic. Thus, in vitro studies have indicated that bromoquinones and bromocatechols may be responsible for some of the covalent binding to protein and reaction with glutathione. However, administration of primary phenolic metabolites does not cause hepatotoxicity. At least seven glutathione conjugates have been identified as metabolites of bromobenzene and its primary phenolic metabolites. 

Bromobenzene is toxic to the liver. It produces two reactive metabolites. Which one is thought to be responsible for the hepatotoxicity 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 ... 

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... 

Wong SG, Card JW, Racz WJ (2000) The role of mitochondrial injury in bromobenzene and furosemide induced hepatotoxicity. Toxicol Lett 116 171-181 Yukinaga H, Takami T, Shioyama SH et al (2007) Identification of cytochrome P450 3A4 modification site with reactive metabolite using linear ion trap-Fourier transform mass spectrometry. Chem Res Toxicol 20 1373-1378... 

---