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At least 19 recordsLinked to original sources
PubMed1984

Identification of 2-bromohydroquinone as a metabolite of bromobenzene and o-bromophenol: implications for bromobenzene-induced nephrotoxicity.

2-Bromohydroquinone was identified as a metabolite of both bromobenzene and o-bromophenol in the rat in vivo and in vitro. Identification was based on high-pressure liquid chromatography and gas chromatography-mass spectrometry. Formation of 2-bromohydroquinone by rat liver microsomes from both bromobenzene and o-bromophenol was increased by treatment of rats with either phenobarbital or 3-methylcholanthrene. Covalent binding of o-bromophenol to rat liver microsomes was inhibited by glutathione and ascorbate but not by superoxide dismutase or catalase. Liver microsomes converted o-bromophenol to 2-bromohydroquinone and covalently bound material, whereas kidney and lung microsomes metabolized o-bromophenol less rapidly. Administration of 2-bromohydroquinone to rats caused a dose- and time-dependent decrease in hepatic and renal glutathione levels, an increase in blood urea nitrogen levels and histopathological changes in kidney without causing any alterations to the liver. The histological changes in the kidney were indistinguishable from those observed after either bromobenzene or o-bromophenol administration. However, the dose of 2-bromohydroquinone required to elicit a similar nephrotoxicity was less than 10% of that of bromobenzene. Thus, 2-bromohydroquinone may play a role in the nephrotoxicity observed after bromobenzene administration. Although the nature of the nephrotoxic metabolite of 2-bromohydroquinone is not known, our present results suggest that 2-bromohydroquinone or a conjugate thereof may be formed in the liver and transported to the kidney where it elicits toxicity.

Animals↗
PubMed1986

Cellular toxicity of bromobenzene and bromobenzene metabolites to rabbit proximal tubules: the role and mechanism of 2-bromohydroquinone.

An in vitro model using a suspension of rabbit renal proximal tubules was developed to investigate the mechanism of nephrotoxicity of bromobenzene. Using oxygen consumption, glutathione concentrations and retention of lactate dehydrogenase activity as markers of toxicity, the rank order of potency was bromobenzene (5 mM) less than 2-bromophenol (2 mM) less than 3-, 4-bromophenol (1 mM) less than 2-bromohydroquinone (0.1 mM). These data support in vivo results and are consistent with the hypothesis that 2-bromohydroquinone or a metabolite thereof is responsible for bromobenzene-induced nephrotoxicity. Inhibitors of cytochrome P-450 and the cyclooxygenase and peroxidase components of prostaglandin H synthase did not protect the proximal tubules from 2-bromohydroquinone-induced toxicity, suggesting that these enzymes do not play a role in 2-bromohydroquinone bioactivation. There is a specific sequence of events in 2-bromohydroquinone-induced toxicity. Early events include decreased glutathione levels and inhibited mitochondrial respiration, whereas an increase in plasma membrane permeability is a late event.

Animals↗
PubMed1992

Bromobenzene-glutathione excretion into bile reflects toxic activation of bromobenzene in rats.

This investigation was designed to determine whether biliary excretion of bromobenzene(BB)-glutathione(GSH) conjugate can be used as an index of in vivo activation of BB. In order to test this hypothesis, the effect of chemicals known to alter the toxicity and biotransformation of BB (i.e., cytochrome P-450 inducers and inhibitors) on the biliary excretion of BB-GSH was studied in rats. BB-GSH was the major BB metabolite in bile. A linear relationship was observed between the dosage of BB administered and BB-GSH excreted into bile, up to a dosage of 250 mumol/kg of BB. Of the inducers tested, phenobarbital, which is known to increase the toxicity of BB, dramatically increased (700%) the rate of biliary excretion of BB-GSH over that in control animals. In contrast, 3-methylcholanthrene, which is known to decrease the hepatotoxicity of BB, decreased the biliary excretion of BB-GSH (56%). Inhibitors of P-450, such as SKF 525-A and piperonyl butoxide which are known to decrease the activation and hepatotoxicity of BB, also decreased the biliary excretion of BB-GSH. These findings are in agreement with the hypothesis that the biliary excretion of BB-GSH reflects the formation of the reactive BB metabolite in liver and the rate of biliary excretion can be used to determine factors that are important in determining the toxicity of BB.

Animals↗
PubMed1985

Influence of zinc chloride on the metabolism and hepatotoxicity of bromobenzene in rats.

In studying the possible interactive effects of various heavy metals on bromobenzene hepatotoxicity and metabolism, zinc chloride (ZnCl2) (0.5, 2.0, and 10.0 mg/kg) was given ip 24 hr prior to ip administration of bromobenzene (2.5 mmol/kg body wt). Animals were sacrificed 48 hr after bromobenzene. A significant increase in the activities of serum transaminases (serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) was observed at 0.5 mg/kg ZnCl2 and such an effect was not observed at the two higher doses of ZnCl2. However, no such increase in the transaminases activities was observed when rats were treated with identical doses of ZnCl2 48 hr before the administration of bromobenzene. When rats were treated with 2 mg/kg ZnCl2 6 hr prior to the bromobenzene dose, a potentiation of the hepatotoxicity due to bromobenzene was again observed, whereas simultaneous treatment of bromobenzene and ZnCl2 produced no such effect. Treatment with ZnCl2 (0.5 mg/kg) 24 hr prior to bromobenzene injection failed to modify the pattern of the urinary metabolites of bromobenzene. When rats were given 50, 250, or 500 ppm of ZnCl2 in drinking water daily for 4 weeks prior to an ip injection of 2.5 mmol/kg bromobenzene, a reduction in the activities of serum transaminases was observed in 250 ppm ZnCl2-treated rats only. Such a reduction in the hepatotoxicity of bromobenzene is accompanied by a simultaneous reduction of the in vivo metabolism of bromobenzene by zinc, as substantiated by reduction of its urinary thioethers as well as of its total urinary metabolites. The present study has shown that changes in the metabolism and hepatotoxicity of bromobenzene depend on the dose of zinc administered, as well as on the temporal relationship between the zinc and bromobenzene administrations. The definitive mechanism responsible for such interactions remains to be elucidated.

Animals↗
PubMed1986

Influence of mercuric chloride on the metabolism and hepatotoxicity of bromobenzene in rats.

When male Sprague-Dawley rats were treated with 1 mg mercuric chloride (HgCl2)/kg, sc 6 hr prior to or simultaneously with a single 2.5-mmole/kg ip dose of bromobenzene and sacrificed 48 hr after the bromobenzene dose, the activities of serum transaminases (SGOT and SGPT) were found to be significantly reduced when compared with those obtained in bromobenzene-alone-treated rats. Similar phenomena were observed when rats were treated simultaneously with 1 or 2 mg HgCl2/kg and 1 mmole bromobenzene/kg, but not when bromobenzene was given 6 hr prior to HgCl2 injection. When 5 mmole bromobenzene/kg and 1 mg HgCl2/kg were given simultaneously to the animals, such an apparent reduction in bromobenzene toxicity was again observed. In each case, HgCl2 alone had no effect on the transaminase activities. HgCl2 (1 mg/kg, sc) treatment reduced the hepatic microsomal cytochrome P-450 content. Treatment with 1 mg HgCl2/kg 6 hr prior to bromobenzene injection (2.5 mmole/kg) significantly reduced the urinary excretion of para- and metabromophenols, and parabromocatechol during 0 to 24-hr period without affecting the urinary thioethers. These data suggest a possible reduction in the rate of formation of bromobenzene epoxide intermediate due to mercury pretreatment, resulting in a lowering of the steady state level of this epoxide so that an inhibition of hepatotoxicity due to bromobenzene could occur. However, simultaneous treatments of HgCl2 and bromobenzene failed to modify the urinary metabolic excretion pattern of bromobenzene. When rats were given 10, 50, and 100 ppm of HgCl2 in drinking water daily for 4 weeks prior to an ip injection of 2.5 mmole bromobenzene/kg and were sacrificed 48 hr after the dose, no changes in SGOT and SGPT activities were observed. These results indicate that changes in the metabolism and hepatotoxicity of bromobenzene due to mercury depend on (a) the dose and time of mercury administration, and (b) the mode of administration of mercury, acute or chronic.

Alanine Transaminase↗
PubMed1988

Antagonism of bromobenzene-induced hepatotoxicity by phentolamine: evidence for a metabolism-independent intervention.

A previous study has revealed that phentolamine markedly antagonizes the bromobenzene-induced hepatotoxicity and lethality in B6C3F1 mice. One potential mechanism by which phentolamine may diminish the bromobenzene-induced hepatotoxicity is by a direct or indirect interference with the metabolism of bromobenzene to toxic metabolites. In the present study, phentolamine cotreatment failed to alter the elimination of bromobenzene from serum or the distribution of bromobenzene to liver. This suggests that phentolamine cotreatment does not indirectly interfere with bromobenzene bioactivation secondary to changes in bromobenzene absorption, distribution, or elimination. Further, a phentolamine concentration 10- to 20-fold greater than those measured in vivo failed to alter the in vitro metabolism of bromobenzene to its ortho- and para-phenolic metabolites. It is believed that para-bromophenol represents the rearrangement product of the hepatotoxic 3,4-epoxide and that ortho-bromophenol is a product of the nonhepatotoxic 2,3-epoxide pathway. Thus, it appears that phentolamine does not antagonize bromobenzene-induced hepatotoxicity by inhibiting the formation of hepatotoxic intermediates, nor by enhancing metabolism via the nonhepatotoxic pathway. On the basis of these studies, we conclude that phentolamine antagonism of bromobenzene-induced hepatotoxicity occurs through a mechanism independent of bromobenzene bioactivation.

Adrenergic alpha-Antagonists↗
PubMed1984

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.

Animals↗
PubMed1987

Effect of a cysteine prodrug (L-2-oxothiazolidine-4-carboxylic acid) on the metabolism and toxicity of bromobenzene: a repeated exposure study.

The relationship between dose, toxicity, and metabolism of bromobenzene and the use of urinary metabolite excretion as an index of internal exposure to the reactive electrophilic intermediate bromobenzene 3,4-epoxide after repeated treatments with bromobenzene in presence or absence of L-2-oxothiazolidine-4-carboxylic acid (OTCA) were evaluated in mice. Repeated treatments with bromobenzene doses of 0.5, 0.75, and 1.0 mmol/kg ip twice a day for 18 d produced a marked reduction in 24-h urinary excretion of bromophenylmercapturic acid and p-bromophenol; this was accompanied by increases in plasma transaminases. Treatment with OTCA (1.0-3.0 mmol/kg) prevented toxicity and enhanced the 24-h urinary excretion of various bromobenzene metabolites by approximately 30-75, 104-145, and 164-269% for bromobenzene doses of 0.5, 0.75, and 1.0 mmol/kg, respectively. The effect of OTCA was further characterized by investigating the metabolism of bromobenzene given as a challenge dose of 4.0 mmol/kg to mice pretreated with bromobenzene and OTCA for 18 d. Pretreatment with bromobenzene reduced the 0- to 6-h urinary excretion of all metabolites after the challenge dose; this effect was virtually reversed by OTCA. It is concluded that repeated bromobenzene administration reduces its own detoxification to mercapturic acid and phenolic metabolites and elicits toxicity. This phenomenon is reversed after OTCA administration. This study further provides evidence that internal exposure to the reactive electrophilic intermediate bromobenzene 3,4-epoxide could be assessed more accurately by summing the urinary excretion of bromophenylmercapturic acid and p-bromophenol after OTCA treatment.

Acetylcysteine↗
PubMed1985

Influence of selenium on the metabolism of bromobenzene and a possible relationship to its hepatotoxicity.

When male Sprague-Dawley rats were treated with sodium selenite (1 mg/kg, sc) 24 hr prior to or simultaneously with bromobenzene (2.5 mmol/kg, ip) and sacrificed 48 hr after the bromobenzene dose, increased levels of the activities of serum transaminases (serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) induced in the bromobenzene-treated rats were significantly reduced in the presence of selenium. However, no such reduction in the transaminases activities were observed when rats were either pretreated with selenite for 48 hr or pretreated with 0.1, 0.2, or 0.5 mg/kg of selenite. Although selenium alone had no effect on the hepatic microsomal drug metabolism, simultaneous treatment of selenite (1 mg/kg) with bromobenzene resulted only an increase in the activity of aniline hydroxylase after 48 hr as compared to that in the bromobenzene-treated group. When rats were given 2.5, 10, and 20 ppm of selenite in drinking water daily for 4 weeks prior to an ip injection of 2.5 mmol/kg of bromobenzene and were sacrificed 48 hr after bromobenzene administration, a reduction in the SGOT activities in all the pretreated groups and a reduction of SGPT activity in 20 ppm selenite-treated group were observed when compared with those in the bromobenzene-treated groups. A dose-dependent increase in hepatic GSH concentrations were observed due to such chronic selenium treatment. Treatment with selenite (1 mg/kg) 24 hr prior to bromobenzene injection (2.5 mmol/kg) increased initially both o and p-bromophenols in the rat urine at 0-7.5 hr without affecting urinary thioethers. On the contrary, the ratio of thioethers to p-bromophenol was significantly higher in both 2.5 and 10 ppm selenite-pretreated (4 weeks) rats as well as a significant increase in the ratio of thioethers to total phenolic metabolites in 10 ppm and an increase close to significant in 2.5 ppm selenite-treated rats were observed initially at 0-7.5 hr urine samples. These results indicate that acute selenium pretreatment under certain conditions, favors increased hydroxylation of the intermediate bromobenzene epoxides, whereas higher detoxification of the epoxides involving hepatic glutathione (GSH)/GSH transferases pathway is more favored due to increased biosynthesis of GSH in certain chronic selenium treated rats.

Administration, Oral↗
PubMed1982

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

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 hepatotoxicity and glutathione depleting ability of bromobenzene are mediated mainly by bromobenzene-3,4-oxide rather than by chemically reactive metabolites of p-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.

Animals↗
PubMed1986

Effect of sodium selenite upon bromobenzene toxicity in rats. II. Metabolism.

The effects of sodium selenite (12.5 or 30 mumol/kg, ip) upon bromobenzene metabolism were examined in male rats treated with selenite at 72 hr prior to bromobenzene exposure (7.5 mmol/kg, ip). The inhibitory nature of selenium treatment upon xenobiotic metabolism and increased production of hepatic thiol suggested that selenite might affect metabolic activation and detoxification of bromobenzene. Selenite treatment lowered in vivo covalent binding of [14C]bromobenzene while the in vitro covalent binding of [14C]bromobenzene in microsomes isolated from selenite-treated rats was unaffected compared to control. When the rate of [14C]bromobenzene decline in whole blood was evaluated in selenite-treated rats over 48 hr after bromobenzene administration, no significant differences were observed when compared to control. Furthermore, values of glutathione conjugates and hydroxylated metabolites of bromobenzene were similar in urine samples collected over 48 hr from selenite and control rats. Mechanistically, reduction of bromobenzene hepatotoxicity by selenite is not mediated through an altered metabolism of bromobenzene, but by alteration of cellular events occurring after metabolic activation.

Animals↗
PubMed1989

Antagonism of bromobenzene-induced hepatotoxicity by the alpha-adrenoreceptor blocking agents phentolamine and idazoxan: role of hypothermia.

A recent study from our laboratory revealed that cotreating mice with the alpha-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 degrees 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 alpha-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 degrees 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 alpha-adrenergic antagonists diminish the hepatotoxicity induced by bromobenzene by a mechanism that is independent of hypothermia.

Adrenergic alpha-Antagonists↗
PubMed1984

Activation and detoxification of bromobenzene in extrahepatic tissues.

Bromobenzene causes hepatic and extrahepatic toxicity in rats. Toxicity is related to the presence of covalently bound material in these tissues. A major bromobenzene metabolite, p-bromophenol, has been shown to give rise to covalently bound material in liver, lung and kidney in vivo, but is not toxic. p-Bromophenol is formed from bromobenzene in liver, lung and kidney microsomes and is subsequently metabolized to 4-bromocatechol and covalently bound material. Bromobenzene-3,4-oxide generated in situ by liver microsomes, is detoxified by kidney, liver and lung cytosol. The results suggest that the kidney toxicity caused by bromobenzene is probably not mediated by either bromobenzene-3,4-oxide or the reactive metabolites of p-bromophenol. In contrast, bromobenzene-3, 4-oxide may play a role in the lung toxicity observed after bromobenzene administration. However, the covalently bound material found in extrahepatic tissues may be derived from both bromobenzene-3,4-oxide or the reactive metabolites of p-bromophenol, which may be formed directly by these tissues or transported there from the liver.

Animals↗
PubMed1985

The role of 4-bromophenol and 4-bromocatechol in bromobenzene covalent binding and toxicity in isolated rat hepatocytes.

4-Bromophenol and 4-bromocatechol are formed as metabolites of bromobenzene in vivo and in isolated rat hepatocytes. Both of these metabolites may potentially contribute to the hepatotoxicity of bromobenzene. Bromobenzene metabolism in hepatocytes isolated from phenobarbital-treated rats forms 0.12 to 0.17 mM 4-bromophenol and 4-bromocatechol in 2 hr, with 1 to 3 mM bromobenzene. The role of activated metabolites derived from 4-bromophenol and 4-bromocatechol in bromobenzene covalent binding and toxicity was investigated with isolated hepatocytes in suspension. The covalent binding of the phenol and the catechol was increased four- to eightfold by the addition of unlabeled bromobenzene. Two-hour incubations of 0.25 mM 14C-labeled 4-bromophenol or 4-bromocatechol with hepatocytes isolated from phenobarbital-treated rats resulted, under these conditions, in no significant toxicity, and approximately 4 and 25%, respectively, of the covalent binding associated with bromobenzene itself. Two- and six-hour incubations with higher 4-bromophenol and 4-bromocatechol concentrations demonstrated that 1 to 3 mM substrate concentrations were required for cytotoxicity. These results show that metabolically produced 4-bromophenol and 4-bromocatechol do not play significant roles in the production of bromobenzene cytotoxicity in isolated hepatocytes, and that they contribute only modestly to bromobenzene covalent binding.

Animals↗
PubMed1987

Effect of a cysteine prodrug, L-2-oxothiazolidine-4-carboxylic acid, on the metabolism and toxicity of bromobenzene: an acute study.

The effect of a cysteine prodrug, L-2-oxothiazolidine-4-carboxylic acid (OTCA), on certain aspects of the metabolism and toxicity of bromobenzene administered acutely to mice was investigated by (i) characterizing the influence of OTCA on the metabolic profile of low and high bromobenzene dose at 0-6, 6-12, and 12-24 h, (ii) determining the effective doses range and administration time for OTCA, as well as the optimum period for urine sampling; and (iii) measuring the efficacy of OTCA for protection against bromobenzene induced toxicity. Coadministration of OTCA and bromobenzene enhanced the urinary excretion of mercapturic acid and phenolic metabolites, during 6-12 h, by approximately 152 and 193%, respectively. Maximum efficacy was observed when OTCA (16.0 mmol/kg) was administered concomitantly with bromobenzene (4.0 mmol/kg). Finally, OTCA administration was found to afford substantial protection against elevation of plasma transaminases used as indices of bromobenzene-induced hepatotoxicity. N-acetylcysteine, another cysteine prodrug, had essentially similar effects on the metabolism and toxicity of bromobenzene. Thus, administration of cysteine prodrugs enhances the urinary excretion of several metabolites of bromobenzene and affords protection against bromobenzene-induced hepatotoxicity.

Acetylcysteine↗
PubMed1984

Protective effect of 16,16-dimethyl prostaglandin E2 on the hepatotoxicity of bromobenzene in mice.

It has been suggested that 16,16-dimethyl prostaglandin E2 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 E2 (50 micrograms/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 E2 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.

16,16-Dimethylprostaglandin E2↗