tert.-Butyl hydroperoxide metabolism and stimulation of the pentose phosphate pathway in isolated rat hepatocytes

Rush, Glenn F.; Alberts, David W.

doi:10.1016/0041-008x(86)90339-x

Cited by 38 publications

(13 citation statements)

References 18 publications

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“…Toxicity occurred without affecting the cell's GSH levels. (Rush & Alberts, 1986). Pretreatment of the cells with diphenylene iodonium, an NADPH:cytochrome P-450 reductase inhibitor (Doussiere & Vignais, 1992), prevented SR 4233 reduction and cytoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…In order to investigate this hypothesis in our hypoxic cell model we monitored SR 4233 reduction in NADPH oxidised hepatocytes. To oxidise cellular NADPH, a small nontoxic dose (50 pM) of t-butyl hydroperoxide (t-BHP) was added to the cell incubation mixture prior to SR 4233 addition (Rush & Alberts, 1986). NADPH levels after this treatment were depressed by >95% for the duration of the experiment.…”

Section: Resultsmentioning

confidence: 99%

“…To oxidise cellular NADPH, t-butyl hydroperoxide (final concentration: 50 jIM) was added to hypoxic cells 5 min prior to the start of the experiment (Rush & Alberts, 1986). NADPH levels at this time were decreased by > 95% as measured by an HPLC method described by Stocchi et al (1984) and stayed depressed for the duration of the experiment.…”

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confidence: 99%

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Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions

O'Brien²

1993

Br J Cancer

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Summary SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is the lead compound of the benzotriazene-di-N oxides which are selectively toxic to tumour cells under hypoxic conditions. However much higher concentrations given to rats caused bone marrow toxicity and necrosis of the low oxygen Zone 3 part of the liver. In the following effects of SR 4233 on hepatocytes under hypoxic vs aerobic conditions have been compared.(

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions

O'Brien²

1993

Br J Cancer

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“…Indeed, a rapid increase in free c ~tosolic calcium concentration occurred in isolated rat hepatoc~tes injured by t-butyl hydroperoxide (tBOOH), an organic ydroperoxide widely used as model compound to induce an (xidative stress [4][5][6][7]. It has also been reported that the activat on of an endonuclease, a process elicited by Ca 2+ changes, t lays a crucial role in DNA fragmentation [8 10].…”

Section: Introduction 2 Materials and Methodsmentioning

confidence: 99%

Oxidative DNA damage by t‐butyl hydroperoxide causes DNA single strand breaks which is not linked to cell lysis. A mechanistic study in freshly isolated rat hepatocytes

1995

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In rat hepatoeytes, DNA damage by t-butyl hydroperoxide (tBOOH) was measured by using the fluorimetric analysis of alkaline DNA unwinding. The electrophoretic profile of genomic DNA suggests single rather than double DNA strand breaks formation. Oxidative DNA modifications, measured as increased 8-hydroxy-deoxyguanosine content, were not detected. Lysis of hepatocytes and DNA strand breaks induced by tBOOH did not correlate, indicating that both processes are not interconm~ted. Since o-phenantbroline prevents against tBOOH-mediated effects on both DNA and membrane integrity, we discussed about a putative role of iron.I~ ey words: DNA fragmentation; Oxidative stress; Organic hydroperoxide; Free radical; Rat hepatocyte This work was undertaken with the aim to study and characterize the DNA damage induced by tBOOH. We further analysed whether this putative DNA damage was linked to the tBOOH-mediated cell death. Oxidant injury was evaluated by following the formation of DNA strand breaks, the time course of LDH leakage and the formation of the DNA adduct 8-hydroxy-deoxyguanosine (8-OH-dG). The extent and the nature of DNA strand breakage were evaluated by the method of fluorometric analysis of the rate of alkaline DNA unwinding (FADU) and by the electrophoretic profile of genomic DNA run on agarose gel, respectively. The cytotoxicity of tBOOH was modulated by using the inhibitor of lipid peroxidation N,N'-diphenyl-p-phenylenediamine (DPPD), the iron chelator o-phenanthroline (oPT) and zinc sulfate and aurintricarboxylic acid (ATCA) as an endonuclease inhibitor.

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“…Cellular GSH redox enzyme activities were measured spectrophotometrically by enzyme-coupled assays for GSH peroxidase (22), GSSG reductase (23), and glucose 6-phosphate dehydrogenase (24). Protein was determined according to Brad-ford (25 (26), the rate-limiting step in the pathway (10,27). The results in To document that the glucose-induced increase in NADPH supported GSSG reduction, cells were pretreated with BCNU, an inhibitor of GSSG reductase (28).…”

Section: Methodsmentioning

confidence: 99%

Glucose regulation of hydroperoxide metabolism in rat intestinal cells. Stimulation of reduced nicotinamide adenine dinucleotide phosphate supply.

Rhoads²

1994

J. Clin. Invest.

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The regulation of intestinal metabolism of t-butylhydroperoxide by glucose was examined in isolated enterocytes from proximal rat intestine. The basal rate of hydroperoxide elimination in control cells was 0.57+0.05 nmol/min per 106 cells, and was increased threefold by 10 mM exogenous glucose (1.74±0.14 nmol/min per 106 cells). Concurrently, cellular NADPH levels increased threefold (1.62+0.40 nmol/ 10' cells vs 0.57±0.14 nmol/106 cells in controls). The glucose effect was blocked by 6-aminonicotinamide and by 1,3-bis-(2-chloroethyl)1-nitrosourea, consistent with glucose stimulation of NADPH production by the pentose phosphate shunt, and of NADPH utilization for glutathione disulfide reduction. The NADPH supply rate was quantified by controlled infusions of diamide, a thiol oxidant. At diamide infusion of 0.05 nmol/min per 106 cells, GSH and protein thiols in control cells were decreased significantly, consistent with a limited capacity for glutathione disulfide reduction. With glucose, cell GSH and protein thiols were preserved at a 10-fold higher diamide infusion which was reversed by 6-aminonicotinamide, supporting the view that glucose promotes glutathione disulfide reduction by increased NADPH supply. Collectively, the results demonstrate that intestinal metabolism of hydroperoxides subscribes to regulation by glucose availability. This responsiveness to glucose suggests that nutrient availability would be an important contributing factor in the detoxication of toxic hydroperoxides by the small intestine. (J. Clin. Invest. 1994. 94:2426-2434

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tert.-Butyl hydroperoxide metabolism and stimulation of the pentose phosphate pathway in isolated rat hepatocytes

Cited by 38 publications

References 18 publications

Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions

Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions

Oxidative DNA damage by t‐butyl hydroperoxide causes DNA single strand breaks which is not linked to cell lysis. A mechanistic study in freshly isolated rat hepatocytes

Glucose regulation of hydroperoxide metabolism in rat intestinal cells. Stimulation of reduced nicotinamide adenine dinucleotide phosphate supply.

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