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J R Gillette

Publications and source records attributed to J R Gillette.

At least 37 records · Page 2Linked to original sources
PubMed1984

Detection and half-life of bromobenzene-3,4-oxide in blood.

Bromobenzene-3,4-oxide can be detected in venous blood of rats by trapping it as the corresponding 35[S]glutathione conjugates. More bromobenzene-3,4-oxide is detected in venous blood of rats treated with phenobarbital and diethyl maleate than in venous blood of rats treated with phenobarbital alone. The half-life of bromobenzene-3,4-oxide in venous blood was about 13.5 s. Bromobenzene-3,4-oxide may contribute to the extrahepatic covalent binding and presumably the toxicity observed after bromobenzene administration. The present technique may be used to determine in blood, the presence or absence of other reactive metabolites that form glutathione conjugates.

Animals↗
PubMed1984

Diffusion of reactive metabolites out of hepatocytes: studies with bromobenzene.

We have developed a simple experimental technique which allows the determination of the relative rates of intracellular inactivation of chemically reactive metabolites and their diffusion out of isolated rat hepatocytes. By using bromobenzene as a model compound we have demonstrated that bromobenzene-3, 4-oxide generated within hepatocytes is sufficiently stable to leave the endoplasmic reticulum in which it is formed, traverse the cytoplasm and cross the cell membrane to the external environment. The addition of varying amounts of protein, which serves as an external sink to trap the epoxide as a covalently bound adduct, permits the calculation of the relative rates at which the epoxide is inactivated within the cells and diffuses out of the cells. As much as 35% of bromobenzene-3,4-oxide is capable of leaving hepatocytes and being trapped as a covalently bound adduct to glutathione (GSH)-transferase B. The extensive diffusion of bromobenzene-3,4-oxide may play an important role in the intercellular toxicity of this compound within the liver and perhaps may contribute to extrahepatic toxicity. The addition of GSH-transferase B to isolated hepatocyte suspensions caused a decrease in the formation of the 3,4-dihydrodiol, p-bromophenol and o- and p-bromophenol glucuronides, an increase in the formation of bromobenzene GSH conjugates, but did not affect intracellular covalent binding. Kinetic analyses of the data revealed that, in the absence of GSH-transferase B, nearly all of the bromobenzene GSH conjugates are formed within hepatocytes as the epoxide is formed, whereas rearrangement of bromobenzene-3,4-oxide to p-bromophenol and hydration to bromobenzene-3,4-dihydrodiol occurs almost exclusively outside the hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗
PubMed1983

Evaluation of the effects of cephaloridine on urate excretion in the rat.

In female Sprague-Dawley rats, the renal clearance of cephaloridine decreased as the plasma concentration of the drug declined from above 10 micrograms/ml to below about 3 micrograms/ml, thus suggesting a saturable tubular reabsorption of cephaloridine similar to that shown previously in man. The effects of cephaloridine (250 mg/kg i.v.) were compared with those shown by a group of rats receiving saline and another group of rats receiving probenecid (250 mg/kg i.v.). Probenecid caused a sustained increase in the urate excretion rate. By contrast, cephaloridine produced a relatively small and transient increase in urate excretion, which may have been caused by its diuretic effect. Thus, it is unlikely that the reabsorption mechanism of urate is the principle mechanism by which cephaloridine is reabsorbed.

Animals↗
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↗
PubMed1982

Stereoselective formation of bromobenzene glutathione conjugates.

Two bromobenzene-glutathione conjugates have been detected as both in vivo and in vitro metabolites of bromobenzene. Separation and purification by high pressure liquid chromatography (HPLC) and analysis by 13C and 1H-NMR spectroscopy indicated that the metabolites are trans-3-bromo-6-(glutathion-S-yl)-cyclohexa-2,4-dien-1-ol and trans-4-bromo-6-(glutathion-S-yl)-cyclohexa-2,4-dien-1-ol. The two conjugates are formed in unequal amounts; over a dose range of 25-500 mg/kg the ratio of the two conjugates excreted into bile in 6 h was 1.6 +/- 0.1 (mean +/- S.E.). Pretreatment of rats with either phenobarbital or 3-methyl-cholanthrene did not significantly alter the ratio of the two conjugates excreted into bile. When bromobenzene was incubated with rat liver microsomes and glutathione, the same two conjugates were formed in the presence but not in the absence of 100 000 x g supernatant. Furthermore, in the presence of 100 000 x g supernatant from control animals, microsomes from rats treated with phenobarbital formed both conjugates 6 times more rapidly than did microsomes from control rats, whereas microsomes from rats treated with 3-methylcholanthrene formed both conjugates less rapidly than did those from control rats. Thus, the data suggest that both conjugates are formed via bromobenzene 3,4-oxide and that their formation requires in liver cytosol.

Animals↗
PubMed1981

An integrated approach to the study of chemically reactive metabolites of acetaminophen.

I have examined in mice the kinetics of covalent binding of a metabolite of acetaminophen, as well as the binding to target tissue (and hence toxic reactions). At low doses, the chemically reactive metabolite seems to be converted to a glutathione conjugate that is ultimately excreted as a mercapturic acid. High acetaminophen doses that deplete available glutathione in the liver lead to toxic reactions. Manipulation of the system with agents that affect either glutathione availability or activity of the operative enzyme system has suggested that a chemically reactive acetaminophen metabolite is the active agent in hepatotoxic reactions from the drug. The chemically reactive intermediate seems to be short lived; it reacts with glutathione and is easily reduced by ascorbic acid. Acetylcysteine prevents liver necrosis caused by acetaminophen, and some possible mechanisms are discussed.

Acetaminophen↗
PubMed1981

A new principle for estimating hepatic blood flow rates.

A new principle for estimating hepatic blood flow rates is demonstrated in steady-state experiments in rats in which p-aminohippurate, labeled with either 14C or 3H, was infused into the portal vein, with simultaneous infusion into the tail vein of the same compound labeled with the other isotope. Hepatic blood flow and hepatic extraction ratios were calculated from measurements of urinary and biliary excretion rates and blood concentrations of each isotope. The principle may be used to calculate hepatic blood flow from measurements of urinary excretion and systemic blood concentrations of drug and metabolite after intravenous injections of radiolabeled drug and precursor.

Animals↗