Effects Of Bromobenzene Research Articles

Alleviation of the hepatotoxic effect of bromobenzene by the Indian traditional herbal formulation Triphala in experimental rats

The present study is an attempt to investigate the efficacy of Triphala in ameliorating the hepatotoxic effects of bromobenzene (BB) in experimental rats. Hepatotoxicity was induced in rats by oral administration of BB (1.57 mg/kg b.w.) and Triphala was given orally at two doses of 250 and 500 mg/kg b.w. for a period of 8 days. The antioxidant status was studied by measuring lipid peroxidation, total reduced glutathione levels and enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) in liver tissue homogenates. In addition, the levels of cytokines such as tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured in serum. The hepatoprotective role of Triphala was compared with that of the standard hepatoprotective agent silymarin. The treatment of BB-intoxicated rats with Triphala showed significant (p < 0.05) increase in the antioxidant status and significant (p < 0.05) reduction in the levels of Tumour Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β). The histopathological findings further confirmed the protective role of Triphala against BB-induced hepatotoxicity in rats. From the results obtained in this study, it can be concluded that treatment with Triphala alleviated the hepatotoxic effect of BB in experimental rats.

Effect of bromobenzene and O-bromophenol on kidney and liver of English sole ( Parophrys vetulus)

1. 1. English sole ( Parophrys vetulus) were injected intraperitoneally with a single dose of 9.8 mmol bromobenzene/kg of fish or 1.9 mmol O-bromophenol/kg of fish, both known renal toxicants in mammals. 2. 2. Kidney, liver, gill spleen, intestines, heart and blood samples were subsequently obtained up to 48 hr post-injection for determination of microscopic lesions, concentrations of selected tissue antioxidants (glutathione and ascorbic acid), and selected serum parameters. 3. 3. Bromobenzene and O-bromophenol were both found to be hepatotoxic in English sole, as indicated by the presence of hepatocellular coagulation necrosis and fatty change in the liver, altered glutathione and ascorbic acid levels in liver tissue, elevated serum aspartate aminotransferase and alkaline phosphatase activity and increased serum glucose and triglyceride levels. 4. 4. No evidence of nephrotoxicity was found in English sole exposed to either toxicant. 5. 5. It is concluded that bromobenzene and O-bromophenol cannot be used as model nephrotoxicants but can be used as hepatotoxicants in English sole.

Reduction of delta-aminolevulinate dehydratase concentration by bromobenzene in rats.

The effects of bromobenzene on delta-aminolevulinate (ALA) dehydratase (EC 4.2.1.24) were examined in rats. The enzyme in the bone marrow was irreversibly inhibited after 12 hours of treatment with bromobenzene (intraperitoneally) without any change in the enzyme concentration. When bromobenzene treatment was prolonged to 72 hours, the concentrations of the enzyme in the bone marrow and in the liver were reduced proportionally to the decrease in the enzyme activity. Neither the activity nor the concentration of ALA dehydratase in the peripheral erythrocytes were reduced even after 72 hours treatment with bromobenzene. These findings indicate that bromobenzene decreases ALA dehydratase activity in a biphasic manner; firstly, through an irreversible inhibition probably due to the formation of mercaptide with the essential SH groups and, secondly, through a reduced synthesis of the enzyme.

Alteration of hepatic glutathione S-transferases and release into serum after treatment with bromobenzene, carbon tetrachloride, or N-nitrosodimethylamine

The effects of bromobenzene, carbon tetrachloride, and N-nitrosodimethylamine (DMN) on hepatic glutathione S-transferase activity were studied in untreated and in phenobarbital- or ethanoltreated. rats. In phenobarbital-treated rats, the isozymic composition of the hepatic cytosolic glutathione S-transferases was changed after giving hepatotoxic chemicals; glutathione S-transferases 2-2(AA), 3-3(A), 1-2(B), 3-4(C), and 4-4 + 5-5(D+E) were present in cytosol from control rats, but only glutathione S-transferases cochromatographing with transferases 4-4 + 5-5(D+E) were detected in rats given carbon tetrachloride or bromobenzene. A marked decrease in hepatic and an increase in serum glutathione S-transferase activity were also observed after carbon tetrachloride or bromobenzene treatment, but little change was seen after giving DMN. On the contrary, in untreated or ethanol-treated rats. DMN administration decreased hepatic glutathione S-transferase activity and caused an elevation in serum glutathione S-transferase activity. The isozymic composition of the hepatic cytosolic glutathione S-transferases after giving DMN to untreated rats was also altered, but the alteration was much less than that observed after giving carbon tetrachloride or bromobenzene to phenobarbital-treated rats. The elevation in serum glutathione S-transferase activity was accompanied by an increase in both serum glutamate-pyruvate transaminase activity and serum bilirubin concentrations. Thus, hepatic glutathione S-transferase activity was altered and released into serum after giving hepatotoxic chemicals, and the alteration in glutathione S-transferase activity was dependent on treatment with phenobarbital or ethanol.

Cytochrome P-450 system dependent depression of δ-aminolevulinic acid dehydratase activity by bromobenzene in rats

Male Wistar rats (200–230 g) were treated with bromobenzene in soybean oil intraperitoneally (i.p.) (4 mmol/kg) once a day for 1 or 2 days while control rats received soybean oil alone. δ-Aminolevulinic acid dehydratase (ALA-D) activity was depressed to 80% and 43% in bone marrow after 24 h and 48 h, respectively. ALA-D activity was also depressed significantly in the liver after the administration of bromobenzene while the activity in peripheral erythrocytes was not altered. After the administration of bromobenzene, the concentration of reduced non-protein sulfhydryls in liver was the lowest at 24 h and increased thereafter. No significant change was observed in the activity of δ-aminolevulinate synthase in liver. The decrease of ALA-D activity was also reproducible in vitro. The 105 000 g supernatant fractions of rat bone marrow lyzates as ALA-D source were incubated with liver microsomes prepared from rats treated with phenobarbital. ALA-D activity was decreased by bromobenzene but no decrease was observed when the microsomes were preincubated with CO to inhibit cytochrome P-450. The effect of bromobenzene on ALA-D purified from rat erythroid cells was studied in incubations containing a reconstituted cytochrome P-450 system prepared from rat liver. The decrease of ALA-D activity was proportional to both the incubation time and to the concentration of P-450 while no decrease was detected when P-450 was inhibited by CO before the incubation.

Dose-dependent metabolic excretion of bromobenzene and its possible relationship to hepatotoxicity in rats.

Male Sprague-Dawley rats received an intraperitoneal injection of 0.25-, 0.5-, 1.0-, 2.5-, and 5.0-mmol/kg dose of bromobenzene in corn oil. The metabolic fate of bromobenzene was studied by measuring its various urinary metabolites 24 h following bromobenzene administration. The hepatotoxicity of bromobenzene was estimated by determination of the serum glutamic-oxaloacetic and glutamic-pyruvic transaminase activities (SGOT and SGPT) 24 h after dosing. Treatment of rats with bromobenzene at up to 0.5 mmol/kg did not influence the transaminase activities, but significant increases in such activities began to manifest at a dose of 1 mmol/kg. However, no further increase in hepatotoxic response was induced on exposure to higher doses (2.5 and 5.0 mmol/kg) of bromobenzene. The urinary excretion of toxic doses of bromobenzene was nonlinear, based on the quantitative composition of various urinary metabolites. Furthermore, the fraction of the dose converted to thioethers, p-bromophenol, m-bromophenol, and total phenolic metabolites decreased with increasing toxic dose, suggesting their formation to be capacity-limited. The ratios of thioethers to total phenolic metabolites, of thioethers to p-bromophenol, and of thioethers to o-bromophenol decreased with increasing dose of bromobenzene. The correlation of the dose-dependent fate of metabolic excretion of bromobenzene with the results of the dose-hepatotoxic response curves supports the conclusion that there exists an apparent threshold dose (approximately 1-2.5 mmol/kg) for the toxic effects of bromobenzene that coincides with saturation of the metabolic pathways involving both glutathione/glutathione S-transferase(s) and formation of certain phenolic derivatives for its detoxification. All these results further suggest a role of a saturable, metabolic activation process involving 3,4-epoxide rather than 2,3-epoxide of bromobenzene in the development of its hepatotoxicity.

Studies on liver toxicants: Influence of bromobenzene on hepatic microsomal drugmetabolizing enzymes in the hamster

The effect of bromobenzene on hepatic microsomal drug-metabolizing enzymes was investigated in hamsters after oral applications of 1.5 and 3.0 g/kg body weight. After 1.5 g/kg a decrease of aminopyrine N-demethylase as well as an increase of hepatic hydroperoxide formation occurred. At 3.0 g/kg, most mixed-function oxidases were inhibited with the exception of ketamine N-demethylase, methylayapanine O-demethylase, and coumarin 7-hydroxylase. Hydroperoxide formation was increased but lipoperoxidation was reduced. Neither glucuronyltransferase 1 nor glucuronyltransferase II were affected by bromobenzene treatment.

The effects of bromobenzene and Carbon tetrachloride exposure in vitro on the phospholipase C activity of rat liver cells

Homogenates were prepared from isolated rat hepatocytes, previously incubated (30 to 120 min) in the presence of bromobenzene (BB), Carbon tetrachloride (CCl 4), or dimethyl sulfoxide (DMSO = control vehicle). Homogenates of hepatocytes incubated with BB and CCl 4 compared to those exposed to DMSO exhibited a rapid increase (two- to five-fold) in their capacity to convert labeled, membrane-bound phosphatidic acid into diacylglycerol. The BB- and CCl 4-dependent increase in diacylglycerol (DG) content, at the expense of phosphatidate, was Ca 2+ dependent and was attributed to changes in cell surface (plasma membrane) enzyme activity since the response occurred primarily in 1000 g cell fractions. when either purified plasma membranes or 1000 g cell fractions, isolated from fresh liver homogenates, were incubated with BB and CCl 4 in vitro, a rise (two- to fourfold) in the conversion of labeled phosphatidate into DG was also observed. These Ca 2+-dependent, BB- and CCl 4-induced changes in hepatocellular glycerolipid content were caused by a BB- and CCl 4-activated phospholipase C which degrades membrane phospholipids. This hypothesis is supported by the observation that 32P-labeled phospholipids of hepatocyte monolayers were rapidly catabolized (10 to 50%) after BB and CCl 4 exposure (5 min). Also, there was an increased conversion of [ methyl- 14C]cytidine diphosphocholine into phosphatidylcholine after cell surface fractions were incubated with phospholipase C, BB, or CCl 4, a change which reflects a rise in hepatocellular DG content. A rapid, BB- and CCl 4-induced rise in hepatocellular phospholipase C activity that degrades cellular phospholipids could disrupt the structure and function of membranes and may represent an early event in toxic substance-related hepatocyte injury.

Studies on liver toxicants. Influence of bromobenzene on hepatic microsomal enzymes in rats.

In acute oral studies, the effect of bromobenzene on hepatic microsomal enzymes was investigated. Neither glucuronyltransferases nor cytochrome c reductase showed significant changes. Most of the mixed-function oxidases studied were inhibited with the exception of ketamine-N-demethylase. The data indicate that bromobenzene or its epoxide acts on cytochrome P-450 but not on all cytochrome P-450 species, and does not affect the reductase and the glucuronyltransferases. Microsomal lipoperoxidation and microsomal H2O2 formation were increased.

Effects of bromobenzene and carbon tetrachloride on the synthesis and release of proteins by perfused rat liver

The effects of bromobenzene and carbon tetrachloride (CCl 4) on the hepatic incorporation of 14C- l-leucine into protein were compared to ascertain the relationship between liver necrosis and impairment of radiolabeled protein synthesis and release caused by these toxicants. Male rats were treated with bromobenzene or CCl 4 and 4 or 12 hr later the livers were removed and perfused in vitro in a recirculating perfusion apparatus. At 4 hr after its administration, CCl 4 only slightly impaired the rate of synthesis of radiolabeled proteins (liver + serum) but markedly decreased the release of radiolabeled proteins into the serum (perfusate). At 4 hr after the administration of bromobenzene, the rates of incorporation of 14C- l-leucine into proteins and the release of radiolabeled proteins were not appreciably changed. At 12 hr after bromobenzene pretreatment, the rate of radiolabeled protein synthesis was not altered when compared to that of control livers, but the release of 14C-labeled proteins into the perfusate was decreased. After pretreatment of rats with phenobarbital, bromobenzene decreased the synthesis and the release of 14C-labeled proteins (4 hr). β-Diethylaminoethyl diphenylpropylacetate (SKF 525-A) and 3-methylcholanthrene (3-MC) did not alter the effect of bromobenzene on the accumulation of total radiolabeled protein synthesis, while SKF 525-A, but not 3-MC, blocked the ability of bromobenzene to decrease the release of 14C-labeled proteins into serum. Since bromobenzene does not alter the rate of 14C-labeled protein synthesis at either 4 or 12 hr after administration, impairment of protein synthesis is probably not a primary cause of bromobenzene-induced liver necrosis. Evidence is presented suggesting that the decrease in the release of 14C- labeled proteins in the perfusate is due to changes in the pattern of protein synthesis as well as to decreases in the rate of protein synthesis.