Bromobenzene In Mice Research Articles

Histopathological and Biomedical parameters Determination in the Protective Effect of Hydroalcoholic Extract of Allium Jesdianum on Hepatotoxicity Induced by Bromobenzene in Mice

Allium Jesdianum (AJ) is the native plant mostly grown in Middle East region that has the excellent pharmacological properties. In this study, we evaluated the hepatoprotective effect of hydroalcoholic extract of AJ on liver injury induced by Bromobenzene (BB) in male mice. Animals were randomly divided into five groups, control group received normal saline plus olive oil, groups 2-4 received(500, 1000 and 2000 mg/kg) AJ extract plus BB for 5 days and 5th group received BB (460 mg/kg). On the fifth day all groups received hexobarbital sodium (25 mg/kg, i.p). it should be noted that sleeping time of all mice were recorded. After 24 hours mice were sacrificed. By serum and tissue biomarkers such as alanine aminotransferase (ALT), aspartate aminotransferase(AST), reduced glutathione(GSH), malondialdehyde(MDA) and histopathological studies were measured. The results showed that BB significantly increased sleeping time, ALT, AST and MDA levels besides and decreased GSH level compared with control group. AJ extract at doses1000and 2000 mg/kg showed a significant alter in all studied endpoints and dose 2000 mg/kg showed a marked improvement in histopathological examination. The present finding showed that administration of the hydroalcoholic extract of AJ could prevent of hepatotoxicity induced by BB via improvement serum and tissue parameters and histopathological alterations in liver tissue.

ISOLATION, CHEMICAL CHARACTERIZATION AND ANTIOXIDANT ACTIVITIES OF A WATER-SOLUBLE POLYSACCHARIDE FRACTION OF TEA (CAMELLIA SINENSIS) FLOWER

ABSTRACT Water-soluble polysaccharide from tea plant flower (TFP) was screened for its biological and biophysical effects. TFP-1, one of the major constituents, yielded after removing the proteins and purification by Sephadex G-100 (Sigma-Aldrich Pty Ltd., Castle Hill, Australia). It was subjected to chemical identification and the result indicated its average molecular weight (132 kDa) and its formation which consisted of xylose, glucose, arabinose and galactose with the molar ratio of 1.0: 2.9: 4.6: 21.8. Presence of TFP-1 displayed reactive oxygen radicals scavenging activity and it showed dose-dependent antioxidant activity by comparing with three commonly used antioxidants. The research showed that administration of TFP-1 for 28d continuously was found not only to be protective on liver lipid peroxidation induced by bromobenzene in mice through increasing the activity of superoxidase dismutase, total antioxidant capacity, but also markedly to attenuate the enhancement of malondialdehyde content in dose-dependent manner. Altogether, these results suggest that TFP-1 could be considered as a potential antioxidant. PRACTICAL APPLICATIONS The resources of tea (Camellia sinesis) flower is abundant in China with low utilization, as tea farmers buried their trim and had little utilization of them. Tea flower is rich in proteins, tea polysaccharides, amino acids, vitamins and other active substances, and its toxicological safety and pesticide residues in volume come up to European standards. At present, commonly low-grade tea is preferred to tea flowers to extract the tea polysaccharide. To make full use of the abandoned tea flower resource to extract polysaccharides can greatly reduce the cost of tea products. Moreover, the research on antioxidant activity of tea flower polysaccharide provides a scientific basis for tea flower as a cheap and effective antioxidant product, additives in food and cosmetic. Secondly, the use of tea flower can also reduce the consumption of tea nutrient and make it turn to vegetative growth, which can improve yield and quality of tea.

Subliminal Fas stimulation increases the hepatotoxicity of acetaminophen and bromobenzene in mice.

The hepatotoxicity of several drugs is increased by mild viral infections. During such infections, death receptor ligands are expressed at low levels, and most parenchymal cells survive. We tested the hypothesis that subliminal death receptor stimulation may aggravate the hepatotoxicity of drugs, which are transformed by cytochrome P-450 cytochrome P-450 into glutathione-depleting reactive metabolites. Twenty-four-hour-fasted mice were pretreated with a subtoxic dose of the agonistic Jo2 anti-Fas antibody (1 microg per mouse) 3 hours before acetaminophen (500 mg/kg) or 1 hour before bromobenzene (400 mg/kg) administration. Administration of Jo2 alone increased hepatic inducible nitric oxide synthase nitric oxide synthase but did not modify serum alanine aminotransferase (ALT), hepatic adenosine triphosphate (ATP), glutathione (GSH), cytochrome P-450, cytosolic cytochrome c, caspase-3 activity or hepatic morphology. However, pretreating mice with Jo2 further decreased both hepatic GSH and ATP by 40% 4 hours after acetaminophen administration, and further increased serum ALT and the area of centrilobular necrosis at 24 hours. In mice pretreated with the Jo2 antibody before bromobenzene administration, hepatic GSH 4 hours after bromobenzene administration was 51% lower than in mice treated with bromobenzene alone, and serum ALT activity at 24 hours was 47-fold higher. In conclusion, administration of a subtoxic dose of an agonistic anti-Fas antibody before acetaminophen or bromobenzene increases metabolite-mediated GSH depletion and hepatotoxicity. Subliminal death receptor stimulation may be one mechanism whereby mild viral infections can increase drug-induced toxicity.

Hispidulin protection against hepatotoxicity induced by bromobenzene in mice

The effects of the natural flavonoid hispidulin (6-methoxy-5, 7, 4′-trihydroxyflavone) on bromobenzene-induced hepatotoxicity in mice were investigated. We found a correlation between liver injury and hepatic lipid peroxidation besides a strong liver glutathione depletion due to the toxicant. Hispidulin at doses between 50 and 150 mg/kg i.p. compared favourably with the reference compound N-acetyl-L-cysteine for inhibition of liver injury and lipid peroxidation. The flavonoid at the highest dose tested was also able to counteract reduced glutathione depletion induced by bromobenzene in starved mice. These hepatoprotective effects can be related to the antioxidant properties of hispidulin.

Antagonism of bromobenzene-induced hepatotoxicity by the α-adrenoreceptor blocking agents phentolamine and idazoxan: Role of hypothermia

A recent study from our laboratory revealed that cotreating mice with the α-adrenoreceptor antagonists phentolamine and idazoxan markedly diminished bromobenzene-induced hepatotoxicity. Subsequent studies also revealed that such cotreatment does not alter the pharmacokinetic disposition of bromobenzene in mice nor its bioactivation to reactive metabolites. In the present study, the possible role of hypothermia in the phentolamine antagonism of bromobenzene-induced hepatotoxicity was investigated. Bromobenzene alone caused a significant, dose-related hypothermia. The high dosage regimen (10 mg/kg per dose) of phentolamine or idazoxan that had been found to be hepatoprotective in earlier studies potentiated this hypothermia and more than doubled the net decrease in core body temperature experienced by the animals. Placing mice receiving bromobenzene in an environment with an ambient temperature of 10°C likewise increased the hypothermia experienced by animals receiving bromobenzene. The magnitude of the net change in core body temperature elicited by exposure to cold was similar to but slightly less than the net change produced by cotreatment with either α-adrenoreceptor antagonist and the magnitude of the hepatoprotection this procedure provided against bromobenzene hepatotoxicity was equivalent to that observed with phentolamine cotreatment. In contrast, a lower dosage regimen of either adrenoreceptor antagonist (2.5 mg/kg per dose) resulted in no additional hypothermia yet still produced a near maximal antagonism of bromobenzene-induced hepatotoxicity. Further, increasing the ambient temperature to 30°C completely reversed the phentolamine-induced (10 mg/kg per dose) increase in hypothermia, but did not affect phentolamine's antagonism of the bromobenzene-induced changes in hepatic glutathione levels, serum alanine aminotransferase activity, or 24-hr mortality. Therefore, we conclude that while the hepatoprotective intervention of phentolamine can be mimicked by an exposure to cold that results in hypothermia, it is clear that α-adrenergic antagonists diminish the hepatotoxicity induced by bromobenzene by a mechanism that is independent of hypothermia.

Nephrotoxicity of phenolic bromobenzene metabolites in the mouse

Bromobenzene, at doses greater than 5.7 mmol/kg, produced renal proximal tubular necrosis and renal functional changes in mice. p-Bromophenol and o-bromophenol were the major urinary phenolic bromobenzene metabolites although m-bromophenol and 4-bromocatechol were also excreted in detectable quantities. With the exception of o-bromophenol, urinary metabolites were excreted primarily as conjugates. 4-Bromocatechol and the 3 bromophenol isomers were nephrotoxicants (measured as increased blood urea nitrogen and decreased accumulation of organic anions by renal cortical slices) but not hepatotoxicants (measured as serum glutamic pyruvate transaminase) in vivo at 0.56 mmol/kg (i.v.). Preincubation of renal cortical slices with each of these bromobenzene metabolites for 90 min resulted in dose-dependent decreases in the accumulation of p-aminohippurate and tetraethylammonium. At 10 μmol/preincubation (2.4 mM), organic ion accumulation was decreased maximally by all bromobenzene metabolites examined while equimolar amounts of bromobenzene were without effect. 4-Bromocatechol was the most potent nephrotoxicant in vitro. Administration of 0.53–2.12 mmol/kg (i.v.) 4-bromocatechol to mice resulted in adose-dependent decrease in renal function while hepatic function was altered only slightly at the higher doses. The renal cortical necrosis produced in vivo administration of 4-bromocatechol could not be distinguishe histogically from that induced by bromobenzene. These results demonstrate that 4-bromocatechol and 3 bromophenol isomers are nephrotoxicants that can be generated from bromobenzene in mice.

Protective effect of 16,16-dimethyl prostaglandin E 2 on the hepatotoxicity of bromobenzene in mice

It has been suggested that 16,16-dimethyl prostaglandin E 2 may have a cytoprotective effect in the liver. To assess this hypothesis, we determined the effects of this prostaglandin on the metabolism and toxicity of bromobenzene in mice. Administration of 16,16-dimethyl prostaglandin E 2 (50 μg/kg s.c., 30 min before, and every 6 hr after, the administration of bromobenzene) did not modify the disappearance curves of unchanged bromobenzene from plasma and liver, and did not modify the amount of bromobenzene metabolites covalently bound to hepatic proteins 1–24 hr after the administration of a toxic dose of bromobenzene (0.36 ml/kg i.p.). The prostaglandin, however, markedly reduced serum alanine aminotransferase activity, the extent of liver cell necrosis, the depletion of glutathione, and the disappearance of cytochrome P-450 after administration of this toxic dose of bromobenzene (0.36 ml/kg i.p.). It also markedly reduced mortality after administration of a lethal dose of bromobenzene (0.43 ml/kg i.p.). We conclude that 16,16-dimethyl prostaglandin E 2 can prevent hepatic necrosis without decreasing the covalent binding of bromobenzene metabolites to hepatic proteins. The mechanism for this dissociation between covalent binding and toxicity remains unknown.

Nephrotoxicity of bromobenzene in mice

I.p. administration of bromobenzene to male mice at doses ranging from 0 to 9.4 mmol kg resulted in a dose-dependent increase in blood urea nitrogen (BUN) and serum glutamic-pyruvic transaminase (SGPT) activity and a decrease in renal cortical accumulation of para-aminohippurate (PAH) and tetraethylammonium (TEA). Induction of renal and hepatic mixed-function oxidases by β-naphthoflavone (BNF) did not result in any alterations in the hepatotoxic or nephrotoxic response to bromobenzene. Renal and hepatic non-protein sulfhydryl (NPSH) concentrations were decreased significantly 1 h after administration of bromobenzene (7.5 mmol kg ) and were maximally depleted in both organs to 18% of control after 7 h. Depletion of renal NPSH by bromobenzene was dose-dependent up to 9.4 mmol kg . Treatment of mice with diethyl maleate (DEM) (0.6 ml kg ) 60 min prior to bromobenzene administration resulted in greater hepatotoxicity, evidenced by increased SGPT, while renal toxicity was unchanged. These data demonstrate that large doses of bromobenzene produce functional alterations in the kidney.