Bromobenzene and p-bromophenol toxicity and covalent binding invivo

doi:10.1016/0024-3205(82)90598-7

Life Sciences

Volume 30, Issue 10, 8 March 1982, Pages 841-848

https://doi.org/10.1016/0024-3205(82)90598-7 Get rights and content

Abstract

A hepatotoxic dose of bromobenzene (3 mmoles/kg) decreases hepatic glutathione concentration in rats by approximately 80% within 5 hr following ip injection. A major bromobenzene metabolite, p-bromophenol at a similar dose did not significantly alter hepatic glutathione levels compared to controls. Twenty four hr after administration, serum glutamate pyruvate transaminase (SGPT) levels were significantly increased by bromobenzene but not by p-bromophenol. After ¹⁴C-bromobenzene administration, a significant amount of covalently bound radiolabel was detected in liver, kidney and small intestine. A small amount of covalently bound radiolabel was also detected in the lung. After a similar dose of ¹⁴C-bromophenol, covalently bound radiolabel was found in liver (62% of the amount detected with ¹⁴C-bromobenzene) and smaller amounts were detected in kidney, small intestine and lung. These data are consistent with the view that the hepatotoxity and glutathione depleting ability of bromobenzene are mediated mainly by bromobenzene-3, 4-oxide rather than by chemically reactive metabolites of p-bromophenol derived from bromobenzene. Covalently bound radiolabel from ¹⁴C-bromobenzene, however, may be derived from both bromobenzene-3, 4-oxide and the nontoxic reactive metabolites of p-bromophenol.

References (28)

W.D. Reid et al.
Exptl. Molec. Path.
(1971)
S.S. Lau et al.
Toxicol. Appl. Pharm.
(1979)
O. Lowry et al.
J. Biol. Chem.
(1951)
S. Hesse et al.
Chem. Biol. Interact.
(1978)
W.F. Greenlee et al.
Toxicol. Appl Pharmacol.
(1981)
R.A. Wiley et al.
Toxicol. Appl. Pharm.
(1979)
E.L. Docks et al.
Biochem. Pharmacol.
(1975)
J.R. Gillette
Biochem. Pharmacol.
(1974)
J.R. Gillette
Biochem. Pharmacol.
(1974)
B.B. Brodie et al.

D.J. Jollow et al.

Pharmacology

(1974)

N. Zampaglione et al.

J. Pharmacol. Exp. Ther.

(1973)

J.R. Mitchell et al.

Res. Commun. Chem. Path. Pharmacol.

(1971)

W.D. Reid et al.

Pharmacology

(1971)

Cited by (63)

Bromobenzene-induced lethal toxicity in mouse is prevented by pretreatment with zinc sulfate
2016, Chemico-Biological Interactions
Citation Excerpt :
Bromobenzene (BB), an industrial solvent and an additive in motor oils, causes necrosis in the liver and kidney. The metabolism and toxicity of BB in liver have been studied in detail [1–5]. BB is subjected to biotransformation in the liver.
In the current study, we evaluated the protective effect of zinc (Zn) against bromobenzene (BB) -induced lethal toxicity. We used Zn because this element is known to be an inducer of metallothionein (MT), which is in turn known to serve as an endogenous scavenger of free radicals. We administered Zn (as ZnSO₄) at 50 mg/kg subcutaneously once-daily for 3 successive days prior to a single intraperitoneal administration of 1.2 g/kg BB in male ddY mice. Our results showed that pretreatment with Zn completely abolished the BB-induced mortality of mice until 48 h. We also found that pretreatment of mice with Zn significantly decreased the functional marker levels and reduced the histological damage both in liver and kidney as assessed at 18 h post-BB. We also showed that pretreatment with Zn enhanced antioxidative activity, resulting in decreased lipid peroxidation in both liver and kidney. Moreover, BB-induced calcium levels were downregulated by pretreatment with Zn. In addition, Zn-induced MT was decreased in Zn + BB-treated animals, implying that MT was consumed by BB-induced radicals. These findings suggest that prophylaxis with Zn protects mice from BB-induced lethal toxicity by decreasing oxidative stress in liver and kidney, presumably by induction of MT, which scavenges radicals induced by BB exposure.
Structure-toxicity relationship and structure-activity relationship study of 2-phenylaminophenylacetic acid derived compounds
2014, Food and Chemical Toxicology
Citation Excerpt :
On the contrary, brominated compounds were often susceptible to P450-mediated metabolism. Several studies have shown that aromatic compounds carrying bromine substitution were metabolized into reactive species and these were proposed as the mechanisms involved in their toxicities (Monks et al., 1982; McDonald and Rettie, 2007). For example, the hepatotoxicity of benzbromarone was linked to the formation of reactive species via metabolic hydroxylation to catechols (McDonald and Rettie, 2007).
2-Phenylaminophenylacetic acid is a widely-exploited chemical scaffold whereby notable NSAIDs such as diclofenac and lumiracoxib were derived. Yet, their clinical usage has been associated with toxicities in the liver. While some studies have attributed toxicities to the bioactivation of both drugs to reactive intermediates, the structural predisposition for toxicity, as well as relationship between this toxicity and COX inhibitory activity has not been elucidated. In this study, we aimed to address their intricate link by synthesizing compounds that possess the 2-phenylaminophenylacetic acid backbone with varying alkyl and halogen substituents at three positions critical to the COX inhibitory pharmacophore. These compounds were subjected to cytotoxicity testing on two liver cell lines of contrasting metabolic competencies. We observed higher toxicity in the more metabolically competent cell line, supporting the role of bioactivation as a prerequisite for toxicity. We have also shown that structural changes on the chemical scaffold exerted pronounced effect on liver cytotoxicity. The most lipophilic and brominated compound (24) was identified as the most cytotoxic of all the compounds. A concurrent determination of their pharmacological activity using COX inhibition assays allowed us to derive a safety profile, which showed that selectivity towards COX-2 negatively affected activity and toxicity.
Idiosyncratic toxicity: The role of toxicophores and bioactivation
2003, Drug Discovery Today
Drugs and chemicals can undergo enzyme-catalyzed bioactivation reactions within cellular systems, with the formation of reactive chemical species. These reactive metabolites can lead to thiol depletion, reversible protein modification (glutathionylation and nitration), further irreversible protein adduct formation and subsequent irreversible protein damage. The incorporation of potentially reactive chemical moieties – toxicophores – within new therapeutic agents should be limited. However, this cannot always be prevented, particularly when the structural feature responsible for toxicity is also responsible for the pharmacological efficacy. The identification and further knowledge of critical levels of thiol depletion and/or covalent modification of protein will aid in the development of new drugs. Importantly, the identification of drug–thiol conjugation should provide a warning of potential problems, yet not hinder the development of a potentially therapeutically useful drug.
Toxicogenomics of bromobenzene hepatotoxicity: A combined transcriptomics and proteomics approach
2003, Biochemical Pharmacology
Citation Excerpt :
Like many xenobiotics, it is a hydrophobic molecule that is subjected to biotransformation in order to enable excretion in the urine. The metabolism and toxicity of bromobenzene in (rat) liver have been described in detail [9–14]. Bromobenzene is subjected to cytochrome P450-mediated epoxidation, followed by either conjugation with glutathione, enzymatic hydrolysis or further oxidation of the phenols, leading to hydroquinone-quinone redox cycling.
Toxicogenomics is a novel approach integrating the expression analysis of thousands of genes (transcriptomics) or proteins (proteomics) with classical methods in toxicology. Effects at the molecular level are related to pathophysiological changes of the organisms, enabling detailed comparison of mechanisms and early detection and prediction of toxicity. This report addresses the value of the combined use of transcriptomics and proteomics technologies in toxicology. Acute hepatotoxicity was induced in rats by bromobenzene administration resulting in depleted glutathione levels and reduced average body weights, 24 hr after dosage. These physiological symptoms coincided with many changes of hepatic mRNA and protein content. Gene induction confirmed involvement of glutathione-S-transferase isozymes and epoxide hydrolase in bromobenzene metabolism and identified many genes possibly relevant in bromobenzene toxicity. Observed glutathione depletion coincided with induction of the key enzyme in glutathione biosynthesis, γ-glutamylcysteine synthetase. Oxidative stress was apparent from strong upregulation of heme oxygenase, peroxiredoxin 1 and other genes. Bromobenzene-induced protein degradation was suggested from two-dimensional gel electrophoresis, upregulated mRNA levels for proteasome subunits and lysosomal cathepsin L, whereas also genes were upregulated with a role in protein synthesis. Both protein and gene expression profiles from treated rats were clearly distinct from controls as shown by principal component analysis, and several proteins found to significantly change upon bromobenzene treatment were identified by mass spectrometry. A modest overlap in results from proteomics and transcriptomics was found. This work indicates that transcriptomics and proteomics technologies are complementary to each other and provide new possibilities in molecular toxicology.
Chemical Mechanisms in Toxicology
2022, DRUG METABOLISM HANDBOOK: CONCEPTS AND APPLICATIONS IN CANCER RESEARCH
Different renal chronotoxicity of bromobenzene and its intermediate metabolites in mice
2021, Biological and Pharmaceutical Bulletin

View all citing articles on Scopus

¹: Present address: National Center for Toxicological Research Jefferson, Arkansas 72079

View full text

Bromobenzene and p-bromophenol toxicity and covalent binding invivo

Abstract

Exptl. Molec. Path.

Toxicol. Appl. Pharm.

J. Biol. Chem.

Chem. Biol. Interact.

Toxicol. Appl Pharmacol.

Toxicol. Appl. Pharm.

Biochem. Pharmacol.

Biochem. Pharmacol.

Biochem. Pharmacol.

Pharmacology

J. Pharmacol. Exp. Ther.

Res. Commun. Chem. Path. Pharmacol.

Pharmacology

Bromobenzene and p-bromophenol toxicity and covalent binding $in$ $vivo$